1 Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, and 3 Portland Veterans Affairs Medical Center, Portland, Oregon 97201-2940; and 2 Diabetes Center, Institute of Clinical and Experimental Medicine, Prague, Czech Republic
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As an important modulator of renal function and morphology, the nitric oxide (NO) system has been extensively studied in the diabetic kidney. However, a number of studies in different experimental and clinical settings have produced often confusing data and contradictory findings. We have reviewed a wide spectrum of findings and issues that have amassed concerning the pathophysiology of the renal NO system in diabetes, pointed out the controversies, and attempted to find some explanation for these discrepancies. Severe diabetes with profound insulinopenia can be viewed as a state of generalized NO deficiency, including in the kidney. However, we have focused our hypotheses and conclusions on the events occurring during moderate glycemic control with some degree of treatment with exogenous insulin, representing more the clinically applicable state of diabetic nephropathy. Available evidence suggests that diabetes triggers mechanisms that in parallel enhance and suppress NO bioavailability in the kidney. We hypothesize that during the early phases of nephropathy, the balance between these two opposing forces is shifted toward NO. This plays a role in the development of characteristic hemodynamic changes and may contribute to consequent structural alterations in glomeruli. Both endothelial (eNOS) and neuronal NO synthase can contribute to altered NO production. These enzymes, particularly eNOS, can be activated by Ca2+-independent and alternative routes of activation that may be elusive in traditional methods of investigation. As the duration of exposure to the diabetic milieu increases, factors that suppress NO bioavailability gradually prevail. Increasing accumulations of advanced glycation end products may be one of the culprits in this process. In addition, this balance is continuously modified by actual metabolic control and the degree of insulinopenia.
reactive oxygen species; endothelial function; renal function; signal transduction; diabetic nephropathy
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
NITRIC OXIDE (NO) IS A PARACRINE mediator with a wide spectrum of physiological actions, including the control of vascular tone, antithrombotic actions, cell cycle regulation, neurotransmission, signal transduction, and inflammation. NO is synthesized during conversion of its physiological precursor L-arginine (L-Arg) to L-citrulline (77). This reaction is catalyzed by a family of enzymes known as NO synthases (NOS) (81). Three NOS isoforms [neuronal (nNOS, NOS1); inducible (iNOS, NOS2); and endothelial (eNOS, NOS3)] have been identified in mammalian tissues. nNOS and eNOS are traditionally viewed as constitutive enzymes, with a limited tissue distribution, exhibiting intracellular Ca2+/calmodulin dependency, although Ca2+-independent activation has been described (29, 34). nNOS and eNOS are responsible for producing NO for a variety of physiological purposes (68). In contrast, iNOS is an inducible enzyme, expressed in all nucleated cells that generate large bursts of NO in response to immunological and certain nonimmunological stimuli. iNOS is usually described as Ca2+ independent, although the presence of Ca2+ enhances iNOS activity (142). To produce NO, NOS enzymes require molecular oxygen and a battery of cofactors and posttranslational modifications (39, 68). Effects of NO are typically mediated by activation of soluble guanylate cyclase, resulting in increased levels of cGMP (85).
NO also acts as a potent modulator of renal function. A wealth of information on renal actions of NO that has amassed during the past two decades has been summarized in several excellent reviews (9, 68). All three NOS isoforms are found in the kidney. nNOS protein and mRNA are found predominantly in the macula densa (MD) region of the distal tubule and renal nerves (7, 64, 127, 150). iNOS mRNA is detectable in most of tubular cells along the nephron (1, 84). eNOS is typically expressed in endothelial cells along the renal vascular tree (7). All three isoforms are expressed in the medulla (88, 104, 123), and medullary NO production exceeds that in the cortex (154). Studies with nonspecific NOS inhibitors, such as L-Arg analogs, demonstrate that renal hemodynamics are very sensitive to NOS inhibition. NO controls both afferent and efferent vascular tone, the ultrafiltration coefficient (28, 159), and medullary blood flow (79), with preferential action on the afferent arteriole (28). In addition, NO has natriuretic actions (4, 79).
As an important modulator of renal function and morphology, the NO system has been extensively studied in the diabetic kidney. However, a number of studies in different experimental settings have often produced confusing data and contradictory findings. In this paper, we will briefly review in vitro evidence on the renal NO system in diabetes; put more emphasis on in vivo evidence, in particular, pointing out the controversies in this literature; and attempt to find some explanation for these discrepancies. Furthermore, based on prevailing evidence, we will propose a unifying hypothesis on the changes in renal NO in diabetes and its role in the pathophysiology of nephropathy.
![]() |
EFFECTS OF DIABETES ON THE RENAL NO SYSTEM IN VITRO |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Determinations of the effects of high glucose or glycosylation products on NO bioavailability in renal cell cultures (143) and in isolated glomeruli ex vivo (22, 23, 112, 146) have been applied by several groups as an in vitro approach to assess the effects of diabetes on the renal NO system. Considering the abundance of endothelial cells in the kidney, we also mention several reports on this cell type. Although not performed directly in renal cells, we assume that the same processes as described by these authors could be active in the kidney and should be discussed in the context of this review (13, 30, 46). In general, in vitro studies have provided important information on the mechanisms whereby high glucose or glycosylation products influence NO bioavailability. These mechanisms include enhanced synthesis or action of the prostanoid thromboxane A2 and PKC activation (22, 23, 46), NO quenching (14, 143), inhibition of both Ca2+-dependent and -independent NOS activities (30, 143), reactive oxygen species (ROS) production (46), and NO capture by glucose (13). Taken together, these studies have suggested a decrease in renal NO production, action, stability, or bioavailability in diabetes. In fact, in vitro studies have provided most of the experimentally available evidence implicating diabetes as a state of renal NO deficiency.
Unlike the previously mentioned approaches, in vitro measurements of
NO-dependent renal vascular reactivity also provide functional aspects
of the renal NO system and are therefore discussed in more detail.
Evidence discussed in this section encompasses studies using various
experimental approaches and models, including the isolated kidney and
isolated arteriolar and renal artery preparations (Table
1).
|
Studies in isolated rat kidneys reported increased (11) or normal (10) vasodilator responses to ACh or metacholine and normal responses to nitroprusside (10, 11). However, other investigators have reported convincing evidence suggesting deleterious effects of diabetes on renal NO-dependent vascular reactivity. Ohishi and Carmines (90) studied isolated kidney preparations using videomicroscopy of in vitro blood-perfused juxtamedullary nephrons to directly assess renal afferent and efferent arteriolar diameters. Diabetic kidneys demonstrated greater baseline afferent diameters, whereas efferent diameters did not differ between diabetic and control rats. Apparently, this model reflects changes in arteriolar diameters in diabetic kidneys similar to those observed in vivo in micropuncture studies (50, 160). Both afferent and efferent responses to the NOS inhibitor NG-nitro-L-arginine (L-NNA) were blunted in diabetic kidneys. The responses to NOS inhibition in diabetic rats were restored by treatment with SOD. These observations suggested decreased NO availability in diabetic glomerular arterioles, possibly due to accumulation of NO-scavenging superoxide anions. Interestingly, this NO-deficient situation was observed in kidneys with decreased afferent arteriolar tone. Corresponding observations have been reported in alloxan-diabetic rabbits. ACh-induced vasodilator responses in preconstricted, microperfused afferent arterioles were impaired in diabetic rabbits, and the defect was corrected by using the SOD mimetic tempol (109). However, using a similar model, Moore et al. (86) reported somewhat different data compared with the two previously mentioned studies. The responses to ACh were unaltered in diabetic arterioles. Although the fractional NG-nitro-L-arginine methyl ester (L-NAME)-induced decrease in afferent diameter was lower in diabetic rats, absolute changes were greater in diabetic vessels. This discrepancy was attributable to differences in baseline diameters between control and diabetic rats. Furthermore, the authors performed direct intraluminal NO measurements and observed a marked increase in NO concentrations in diabetic vessels after perfusion with a high-glucose perfusate. The authors also explored the vasoactive effects of advanced glycation end products (AGEs). The AGE-containing perfusate induced no changes in diabetic vessels, although it blunted responses to ACh. Thus these findings are only partially consistent with previously mentioned studies by Bucala et al. (14) and do not suggest a substantial role for AGE in NO quenching.
An interplay between NO and ANG II was addressed by Schoonmaker et al. (111). Control afferent arterioles had enhanced vasoconstrictor responses to ANG II when pretreated with L-NNA. In contrast, L-NNA-treated and untreated arteries harvested from diabetic rats demonstrated no differences in ANG II-induced vasoconstriction. Moreover, responses of efferent arterioles were similar in control and diabetic rats (111). These observations corresponded to previous findings in rabbit afferent arteriolar preparations microperfused with a normal and high-glucose (30 mM) perfusate (6) and suggested attenuated NO action in counterbalancing the effects of ANG II specifically in afferent arterioles in diabetes and/or hyperglycemia.
Diabetes-associated changes in the NO system have also been investigated in isolated renal arteries. It is likely that observations in renal arteries reflect changes in the vascular system in general rather than contribute to an understanding of specific renal processes. However, controversial findings in this area may signal some specific features of the renal arteries compared with other large-conduit vessels that usually display diabetes-induced defects in endothelium-dependent vasodilation (99). Dai et al. (25) reported that the defect in ACh-induced vasodilation in diabetic rats was ameliorated by pretreatment with a hydroxyl radical scavenger or with a blockade of prostaglandin H2-thromboxane A2 receptors. Corresponding to studies in other experimental settings (23, 90, 109), these data suggest an impairment of NO endothelial production or action in diabetic arteries, possibly mediated by the increased production of ROS and prostanoids that oppose the effects of NO. However, more recent studies in that model found unchanged responses to ACh in renal arteries from insulin-treated diabetic rats preconstricted with serotonin and even enhanced responses to insulin compared with controls (130, 131). In contrast to data by Dai et al. (25), enhanced responses to ACh and to NOS inhibition have also been reported in renal arteries harvested from untreated alloxan-diabetic rabbits (3).
Unlike the studies in cultured renal cells, evaluation of renal vascular reactivity in vitro has provided more controversial evidence, suggesting enhanced, normal, or decreased NO synthesis and activity in the diabetic kidney (Table 1). These contrasting findings cannot be explained by species differences, differences in duration of diabetes, metabolic control, or the presence or absence of insulin treatment.
One of the factors that could possibly explain differences among at least some of these studies could relate to the method of preconstriction of isolated vessels. There is evidence suggesting that different vasoconstrictor stimuli may alter responses to ACh in afferent arterioles (43). Different constrictors may also exert variable effects on basal vascular tone and, as in the case of serotonin, even activate eNOS (107).
Several caveats of in vitro approaches in evaluating the renal NO system in diabetes in general merit consideration. The in vitro studies may not precisely reflect the diabetic milieu, which is determined not only by high glucose. For example, most of the in vitro evidence regarding the effects of glucose on cellular NO systems has been obtained by using media glucose concentrations from 25 to 33 mM. The clinical correlate would be severely decompensated diabetes, which is known to be associated with renal vasoconstriction as a result not only of specific effects of glucose on renal cells but also of physiological compensation for volume depletion and electrolyte wasting (50). However, as specifically discussed below, early stages of nephropathy are characterized by glomerular hyperperfusion, which has important pathophysiological implications and is prominent in the more clinically applicable model of moderate hyperglycemia (15-20 mM) (52, 162). Consequently, it is beneficial to use an in vitro approach to precisely model a particular condition and obtain answers to specific questions. However, the in vitro data should be interpreted with caution, considering functional alterations typical in the early stages of diabetic nephropathy.
Several in vitro studies also focused on the effects of hyperglycemia on iNOS-derived NO in renal cell cultures (113). Considering the relatively weak in vivo evidence for the role of iNOS in diabetes-induced alterations in the renal NO system, these papers are not discussed in this review. Consequently, we also do not discuss in vitro studies in mesangial cells. With respect to prevailing evidence, this cell type does not express constitutive NOS (68).
![]() |
EFFECTS OF DIABETES ON THE RENAL NO SYSTEM IN VIVO |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Expression of NOS Isoforms in the Diabetic Kidney In Vivo
A number of studies have examined renal NOS expression in diabetes in vivo (Table 2). Some of the studies mentioned in this section combined measurements of NOS expression with renal hemodynamics and will be discussed further in the following sections. Choi et al. (19) found markedly increased renal cortical expression of all NOS isoforms in streptozotocin (STZ)-diabetic rats; medullary expression of NOS was not different from controls. Another group (118) found enhanced immunohistochemical expression and NADPH diaphorase staining, reflecting constitutive NOS activity, in endothelia of afferent but not efferent arterioles of STZ-diabetic rats. Enhanced NADPH diaphorase staining was associated with increased afferent diameter, increased glomerular filtration rate (GFR) assessed by creatinine clearance, and glomerular hypertrophy. These changes were corrected by insulin treatment or by treatment with L-NAME. In accordance with the previous report, Veelken et al. (141) reported increased cortical eNOS expression in untreated hyperfiltering diabetic rats. In addition, increased medullary expressions of nNOS and eNOS were found in the medulla of diabetic rats treated with insulin (115).
|
Early studies that focused on nNOS immunoreactivity in MD cells reported less intense immunohistochemical staining for constitutive NOS (presumably nNOS) in MD and glomerular arterioles in rats with diabetes for various durations (157). In concert with those findings, Keynan et al. (60) reported decreased nNOS mRNA and diaphorase MD staining in rats at 7 days of diabetes. Furthermore, they found no differences in cortical eNOS between control and diabetic rats. Unlike most of the studies dealing with this issue, they found decreased urinary nitrite/nitrate excretion (UNOxV) in diabetic rats compared with controls.
Most recent analyses also do not provide unequivocal evidence. Ishii et al. (54) found no differences in cortical expression of NOS isoforms between diabetic animals and controls. Diaphorase staining also did not differ among groups. Another study (92), using whole kidney samples, found no change in nNOS and increased eNOS in female rats after 4 wk of diabetes. In addition, whole kidney eNOS and iNOS mRNAs evaluated by RT-PCR were unchanged in diabetic rats (112). Finally, increased eNOS expression was found in purified renal vascular trees of diabetic rats (26).
Thus it appears that consensus can be reached with respect to eNOS expression. Most of the available evidence suggests increased expression of this isoform in the diabetic renal cortex. There are disparate findings concerning nNOS, suggesting increased, normal, or decreased expression (Table 2). It should be noted that a decrease in nNOS in the diabetic renal cortex has been observed only in rats without insulin treatment. With the exception of one study (19), iNOS cortical protein and mRNA expression have been found to be unchanged (54, 112) or barely detectable (119, 141) during the hyperfiltering stage. Two observations suggest that iNOS is detectable in the renal cortex of rats with long-term diabetes. iNOS was immunohistochemically detected in glomeruli of rats after 1 yr of diabetes but not in control age-matched animals (119). Another long-term study (32 wk) demonstrated weak glomerular expression in both control and diabetic rats (116) but no differences between the groups.
Disparate findings have also been reported in studies that determined renal NOS activity by a citrulline generation assay. Keynan et al. (60) found decreased cortical NOS activity. However, one might question the validity of the assay in this particular study because NOS activity was not detectable in the medulla, which should have much higher NOS activity than the cortex (154). In contrast, Omer et al. (91) and Ishii et al. (54) found increased cortical NOS activity in diabetic rats. Importantly, these studies differed in the absence (60) or presence (54, 91) of insulin treatment.
![]() |
ROLE OF NO IN RENAL HEMODYNAMIC ALTERATIONS IN DIABETES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Early stages of diabetic nephropathy are associated with increases
in GFR and variable increases in renal plasma flow (RPF) and filtration
fraction, both clinically and experimentally (5). This
"diabetic hyperfiltration" has been implicated in the pathogenesis of diabetic nephropathy both in humans as well as in animal models of
diabetes (49, 83, 105, 160, 161). At the single-nephron level, diabetic hyperfiltration is characterized by disproportionately decreased afferent arteriolar resistance, resulting in elevated glomerular capillary pressure (PGC) (50, 90,
160). Considering the renal hemodynamic actions of NO, this
substance is a good candidate for mediating diabetic hyperfiltration.
In this section, we will discuss studies exploring acute
hemodynamic effects of modulation of NO synthesis in vivo (Table
3).
|
Most of the evidence concerning the role of NO in control of renal hemodynamics in diabetes was obtained using nonspecific NOS inhibitors. More recently, several studies have attempted to test the activity of individual NOS isoforms with newly available isoform-specific inhibitors. In a number of these studies, GFR and RPF were measured as clearances of inulin and PAH using constant-infusion techniques. Despite the explosive developments in molecular biology, we consider such evidence as the gold standard when evaluating the role of a particular substance in the control of renal hemodynamics in vivo. In addition to measurements of renal hemodynamics, these studies have also often relied on measurements of UNOxV and urinary cGMP as markers of renal NO production.
To our knowledge, the first in vivo evidence indicating that modulation of NO synthesis could influence renal hemodynamics in diabetes was reported in an abstract by King et al. (62). Their preliminary data showed a major renal vasoconstrictor effect of a pressor dose of NOS inhibitor, suggesting greater NO dependence of renal hemodynamics in diabetic compared with control rats. Full papers by other groups addressing this issue followed shortly. Bank and Aynedjian (8) found an increase in UNOxV in hyperfiltering diabetic rats, consistent with increased NO production. However, when administered increasing doses of NLA, both diabetic and normal rats had similar decreases in GFR and RPF. Despite these disparate findings, the authors concluded that NO synthesis was increased in hyperfiltering diabetic rats and that excessive NO synthesis contributed to hyperfiltration. Tolins et al. (128) also found increased UNOxV in hyperfiltering diabetic rats. However, NOS inhibition with L-NAME normalized GFR in diabetic rats and induced greater vasoconstrictor responses under various perfusion pressures. Importantly, perfusion pressure was modified independently of the systemic blood pressure changes that would usually be associated with systemic NOS inhibition. Thus both excretion of stable metabolites of NO and renal hemodynamic responses suggested enhanced renal generation of NO and its contribution to the pathogenesis of diabetic hyperfiltration.
We evaluated the effects of L-NAME in conscious control and hyperfiltering diabetic rats (63). At a low dose of L-NAME, diabetic rats demonstrated a blunted mean arterial pressure (MAP) response and a proportionately significant reduction in GFR and RPF compared with controls. At a supramaximal dose, the L-NAME-induced rise in MAP was similar in diabetic and control rats. However, renal vasoconstriction was greater in the diabetic animals. UNOxV was increased in diabetic rats and significantly reduced by low-dose L-NAME. Furthermore, diabetic rats demonstrated no response to the NO donor glyceryl trinitrate (GTN), which induced significant renal vasodilation in control rats. We interpreted the lack of a GTN effect in the diabetic kidney as a further indication of enhanced NO production and/or signaling that cannot be significantly altered by additional NO. Interestingly, this phenomenon was later quoted in support of impaired NO actions in the diabetic kidney (96). These results, in accordance with the previous study, suggested a role for NO in the pathogenesis of hyperfiltration and increased renal NO generation in diabetes. Similar data, i.e., significant reduction in hyperfiltration in anesthetized diabetic rats in response to L-NAME, were then reported by Mattar et al. (78) and in several studies that focused on other issues (118, 141). Furthermore, extensive studies by Omer et al. (91) confirmed our findings in virgin and pregnant normal and diabetic rats. Both groups demonstrated marked hyperfiltration that was nearly normalized by L-NNA. Moreover, substantial increases in RPF in diabetic animals, further enhanced by pregnancy, also showed marked sensitivity to NOS inhibition. Similar to our studies (63), the MAP response was attenuated in virgin diabetic animals compared with controls. These hemodynamic observations were associated with parallel changes in UNOxV and increased baseline NO renal generation as assessed by the citrulline generation assay. Interestingly, this group also found an enhanced response to ACh in aortic rings from diabetic rats (91).
Most recently, the effects of nonspecific NOS inhibition were evaluated in hydronephrotic kidneys of control and moderately hyperglycemic female rats at 6 wk of diabetes (26). This model was used to allow intravital microscopy for evaluations of changes in renal vascular diameters. Increased vasoconstrictor responses to L-NAME in diabetic rats, suggesting local hyperproduction and activity of NO, were apparent in all segments of the renal vasculature. One might argue that using the hydronephrotic kidney model involves factors other than the diabetic milieu that would alter local NO production and therefore complicate interpretation of the results. However, renal vascular responses were in good accord with eNOS protein expression determined in vascular trees of intact kidneys.
Not all authors have found enhanced whole kidney hemodynamic responses to NO inhibition. Using Doppler probes, Kiff et al. (61) found similar responses to L-NAME in conscious control and diabetic rats. Another study (37) reported rather controversial observations. In basal conditions, diabetic rats demonstrated marked increases in creatinine clearance (CCr) and UNOxV compared with controls. L-Arg increased UNOxV in controls but not in diabetic rats. L-NAME had no effect in controls but decreased UNOxV in diabetic animals. In further studies, uninephrectomized control and diabetic rats were evaluated after 60 min of renal ischemia. Control rats responded with less severe decreases in CCr and higher UNOxV, whereas diabetic animals demonstrated an opposite trend that was further aggravated by L-NAME. Despite the finding in basal conditions, the authors concluded that renal NO production is defective in diabetes (37). Given the pathophysiological complexity of ischemic renal failure, it is also unclear whether kidneys after 60 min of total occlusion of the renal artery represent an appropriate model for studies of the NO system in diabetes.
Pflueger et al. (96) applied videomicroscopy in control and STZ-diabetic rats to assess cortical and medullary blood flow in superficial cortical capillaries and papillary vasa recta. Diabetic rats demonstrated basal increases in these parameters, as well as increases in GFR (measured as inulin clearance in the contralateral kidney) and plasma NOx levels. UNOxV did not differ between control and diabetic rats. Despite increased blood flow and a higher GFR, diabetic rats showed attenuated responses of the cortical and papillary microcirculations to both systemic NOS inhibition with L-NMMA and stimulation of NO synthesis with L-Arg. The unresponsiveness of NO synthesis inhibition was greatest in cortical capillaries. Thus, despite baseline hyperperfusion, these data suggest a defect in renal, and particularly renal cortical, NO production or action in diabetes in vivo. In a parallel study, the same group reported increased sensitivity of diabetic renal vasculature to adenosine due to defective counterregulatory NO production (97). Of note, increases in GFR observed in contralateral kidneys in diabetic rats were normalized by NOS inhibition. It is not clear how measurements of a single capillary diameter and red blood cell velocity relate to the traditional methods for determining renal function, because the changes in GFR were not reflected by the effects of NOS inhibition on cortical capillaries in the contralateral kidney.
Whereas the preceding studies relied on nonspecific NOS inhibitors, the contribution of individual NOS isoforms to NO production in the diabetic kidney has only recently been evaluated. Research in this direction has been accelerated by the availability of new inhibitors that selectively block NOS isoforms.
Studies by Wang et al. (146) represent a less frequently used approach to investigate in vivo whole kidney responses to NO modulation. In these studies, the authors evaluated responses to intravenous infusion of ACh. Therefore, these studies could be interpreted as exploring isoform-specific NO production (eNOS). The renal vasodilator response to ACh was diminished in diabetic rats but not in normoglycemic diabetic rats. Acute treatment with insulin did not restore the response to ACh, although the blood glucose level was normalized. These in vivo experiments further supported the in vitro data by this group (146), suggesting reduced NO bioavailability and/or impaired signaling in the renal vascular endothelium and the previously discussed possible defects in receptor-mediated eNOS stimulation.
There is abundant literature suggesting defective endothelium-dependent (i.e., eNOS dependent) NO production or function in diabetes, in apparent contrast to observations of substantial NO dependency of renal hemodynamics in hyperfiltering rats, as revealed with nonspecific NOS inhibitors. We hypothesized that increased renal nNOS activity could explain this paradox. This isoform is expressed in MD cells (7, 150), and nNOS-derived NO in MD decreases predominantly afferent arteriolar tone (51, 150), contributes to control of intraglomerular pressure (124, 150), and counteracts afferent vasoconstriction induced by activation of tubuloglomerular feedback (TGF) (51). We explored the acute effects of systemic nNOS inhibition with the specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) (89) in diabetic rats (66). SMTC induced stronger renal vasoconstriction responses in diabetic compared with control animals. Renal vasoconstriction was partly opposed by ANG II AT1 receptor blockade, suggesting an interaction of nNOS-derived NO with ANG II. Further studies were designed to diminish the possible systemic effects of SMTC (64). When administered directly into the abdominal aorta above the left renal artery, SMTC did not influence MAP but nearly normalized GFR in hyperfiltering diabetic rats. These observations indicate that nNOS contributes to altered renal NO production and hemodynamics in experimental diabetes. Renal hemodynamic effects of SMTC were attenuated in normoglycemic diabetic rats, suggesting that alterations in nNOS activity are related to the level of metabolic control. Moreover, the nonspecific NOS inhibitor L-NAME did not influence GFR but further decreased RPF in diabetic rats pretreated with SMTC. These data suggest that nNOS is the major isoform responsible for hyperfiltration, although other isoforms act in concert with nNOS in the control of renal perfusion.
Similar results regarding the role of nNOS were more recently reported by Ito et al. (55), using a different nNOS inhibitor [7-nitro indazole (7-NI)]. Furthermore, data by Schwartz et al. (112), showing enhanced renal hemodynamic response to a nonspecific NOS inhibitor, in conjunction with an absence of response to the iNOS blocker L-N6-(1-iminoethyl)lysine (L-NIL) and unchanged renal iNOS and eNOS mRNA expressions, indirectly point to nNOS. Further indirect support for the role of nNOS in diabetic alterations in glomerular hemodynamics can be derived from observations that the activity of TGF is blunted in diabetes (135). The physiological roles of nNOS-derived NO (51) and its suggested higher production by MD cells in diabetes are consistent with this abnormality. In addition, Veelken et al. (141) reported the lack of effect of a selective iNOS inhibitor, L-NIL, in contrast to the effect of L-NAME, on renal hemodynamics in conscious STZ-diabetic rats. Because cortical eNOS expression was increased in diabetic rats, the authors suggested the role of eNOS in the pathogenesis of hyperfiltration. However, these findings do not exclude the possibility that nNOS is involved in the process, because the reduction of GFR was achieved with a nonspecific NOS inhibitor.
Unlike in vitro and in vivo studies focusing on renal NOS expression, we are able to identify some differences in in vivo hemodynamic studies, suggesting enhanced renal NO production/activity in diabetes and those studies reporting opposite data. There is a clear distinction between the two lines of evidence with respect to methods of measurements of renal function. In those studies that used formal clearance techniques to determine GFR and RPF, diabetic rats demonstrated hyperfiltration and enhanced responses to NOS inhibition, suggesting increased renal production and/or activity. In contrast, studies with contrary evidence used either CCr or techniques requiring extensive instrumentation (96, 97).
Another factor that could influence the outcome of these studies is the presence or absence of insulin treatment. Those investigators who used insulin treatment to achieve moderate hyperglycemia have generally found hyperfiltration and enhanced hemodynamic responses to NOS inhibition. One might argue that decreased renal hemodynamic responsiveness to NOS inhibitors has also been observed in moderately hyperglycemic rats. However, in those studies, despite an absence of exogenous insulin treatment, residual endogenous insulin secretion prevented severe hyperglycemia (96, 97). As discussed below, the combination of moderate hyperglycemia and exogenous insulin treatment may be a crucial factor creating the milieu for NO-dependent diabetic hyperfiltration. This interpretation is in accord with the available micropuncture data (110). An exception to this rule may be the elegant studies of Carmines et al. (90, 111). However, the technique used by that group (evaluation of arteriolar diameters in isolated blood-perfused nephrons) is still an in vitro technique. Consequently, arterioles and glomeruli in diabetic animals are not exposed to the same metabolic milieu as occurs in vivo.
Many in vivo studies have buttressed their conclusions of enhanced renal NO production by demonstration of increased UNOxV. However, these measurements should be interpreted with caution. Considering present knowledge of the distribution of NOS activities in the kidney (154), and studies by Suto et al. (120) that directly addressed this issue, it is clear that measurements of urinary NOx can hardly reflect NO changes in the cortex. Although some attempts to directly determine renal NO production in vivo have been communicated, our present knowledge still relies mostly on indirect indicators of renal NOS activity. Direct measurements of NO in the kidney represent some of the challenges for future research.
Pieper (98) has suggested that the duration of diabetes is an important determinant for NO production in the vascular system, evolving from an increase during the early stages, followed by a period of normal production, and then to a decrease in production as the duration of the disease increases. However, this construct does not really explain the discrepancies in published data regarding either renal NOS expression or in vivo studies of hemodynamics. The evidence remains controversial irrespective of the duration of diabetes.
Effects of Long-Term Modulation of NO Synthesis in the Diabetic Kidney
One would expect that long-term modulation of NO would ultimately answer many questions regarding the role of NO in the development of diabetic nephropathy. However, even these types of studies have not provided unequivocal data. Several studies have suggested a nephroprotective role of NO in the development of nephropathy in diabetic rats. Reyes et al. (103) found lower proteinuria and amelioration of hyperfiltration in STZ-diabetic rats after 14 wk of L-Arg treatment. However, this study reported several findings that are difficult to interpret. Administration of L-Arg did not lead to increased cGMP and UNOxV; in fact, these parameters were lower in treated rats. Thus the study failed to provide proof that the decrease in proteinuria was mediated via increased renal NO production. Paradoxically, in both vehicle- and L-Arg-treated diabetic rats, urinary protein excretion was higher at baseline than after treatment, and the achieved values exceeded levels seen in animals with severe glomerulosclerosis. Furthermore, histological evaluation did not reveal any differences in glomerulosclerosis scores between L-Arg-treated and vehicle-treated rats.Further evidence for a possible renoprotective role of NO in
diabetes was reported by Craven et al. (21).
STZ-diabetic rats received nonpressor doses of
L-NAME for 4 wk. At the end of the study,
L-NAME-treated rats had slightly but significantly higher albuminuria, although still in the microgram range. Importantly, renal
transforming growth factor- (TGF-
) was increased in treated rats.
However, the study was too short to determine whether chronic nonpressor L-NAME could accelerate the course of
nephropathy. This issue was addressed by Soulis et al.
(116), who found no effect of chronic (6 mo) treatment
with a nonpressor dose of L-NAME on the progression of
nephropathy in STZ-diabetic rats. In addition, corresponding to our
acute studies (64), our preliminary data suggest that
long-term nNOS inhibition with a nonpressor dose of SMTC modestly
retards development of renal injury in diabetes (67).
![]() |
POSTRANSLATIONAL MODULATION OF NOS ACTIVITY: IMPACT OF DIABETES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the previous sections, we focused on individual studies, pointed out some differences, and attempted to find some explanation for disparate findings in studies with generally similar designs. In the following paragraphs, we will discuss additional controversial issues that arise when one analyzes particular aspects of renal NO physiology and pathophysiology with respect to the pathogenesis of diabetic nephropathy. To shed light on the issues, we will include some evidence from the extrarenal literature. Although we will discuss the following issues separately, it is apparent that they represent a conglomerate of interacting mechanisms.
Changes in eNOS Conformation and Generation of ROS
To function as NO-producing enzymes, NOS requires a battery of cofactors, conformational changes, and fatty acid acylations responsible for membrane targeting of the enzyme (reviewed in Refs. 39 and 81). A traditional pathway of eNOS activation involves receptor stimulation by agonists such as ACh or bradykinin, resulting in a mobilization of intracellular Ca2+ and consequent interaction of calmodulin and eNOS, releasing the enzyme from an inhibitory complex with caveolin-1 (58). On more prolonged agonist stimulation, eNOS may be released from its membrane location and translocated to other subcellular compartments. This reversible translocation may represent a mechanism to downregulate or disconnect the enzyme from receptor occupancy (76).In addition to synthesizing NO, purified NOS catalyzes
O
Enhanced production of ROS appears to be an important mechanism in the
pathophysiology of diabetic complications, including nephropathy. Their
role has been validated in long-term studies (71, 80). ROS
may be involved in diabetes-induced alterations in lipids and proteins,
cellular signaling (40), as well as inactivation of NO.
After generation by these enzymes, O, or may be transformed into the more stable radical
H2O2. This reaction is catalyzed by SOD.
H2O2 is further metabolized by catalase. Two
studies determined nitrosylated protein (NT) expression in diabetic
kidneys by Western blotting as a measure of ONOO
formation (54, 92). Both studies found increases in this parameter in diabetic kidneys, indicating enhanced interaction between
NO and O
was formed in that compartment. Postmortem human data show increased NT
formation in proximal tubules of patients with long-standing diabetes
compared with kidneys from patients with glomerulonephritis or normal
kidneys (125). Thus far, then, there is no proof of enhanced NT formation in the renal vascular tree in diabetes.
There are several sources of ROS (108). Some investigators
have addressed the question of whether eNOS could be an important source of ROS in diabetes. Cosentino et al. (20) reported
increased eNOS expression associated with parallel increases in NO and
O
In an aforementioned in vitro report, L-Arg had improved basal, but not ACh-stimulated, cGMP production by isolated glomeruli (23). This phenomenon suggests a specific glucose-induced defect in receptor-mediated eNOS activation, mediated by factors already mentioned (23) or, for example, by ROS-induced alterations in eNOS-caveolae interactions, eNOS cellular localization, and cofactor integrity (56, 95).
The fact that eNOS undergoes important posttranslational changes and
protein-protein interactions documents the importance of more detailed
experimental approaches in evaluating NOS expression in the diabetic
kidney. For example, the changes in renal expression of NOS mRNA or
total protein in the diabetic kidney may not reflect the functional
status of the enzyme. Because most of the evidence concerning eNOS
expression in the diabetic kidney has not taken into account the
quaternary structure of NOS and other posttranslational modifications,
it is difficult to draw links between most of the available knowledge
concerning renal NOS expression and its function. Considering the
disparate findings in some studies focusing on eNOS-mediated vascular
reactivity in diabetes, it is possible that the results depend on the
actual balance between NO and O
We have recently attempted to address some of these issues. Our preliminary data suggest alterations in some of those posttranslational modifications and other functionally important characteristics, such as decreased formation of the NO-producing eNOS dimer, alterations in membrane eNOS targeting, and eNOS- caveolin-1 interaction in the diabetic renal cortex (65). Further documenting the need for more detailed analytic approaches to assess renal NOS, a preliminary report by Carmines et al. (15) demonstrated reduced renal cortical expression and function of heat shock protein 90 in diabetes, another protein cofactor facilitating eNOS catalytic activities.
Considering the data from long-term studies (71, 80), one
would not question the contribution of ROS to the development of
nephropathy, although beneficial effects of antioxidant treatment remain to be established in large clinical trials. However, the data
suggesting the contribution of NO-ROS interactions to alterations in
renal vasomotor function in diabetes raise several questions. First,
this evidence suggests that O
Second, we are not aware of any evidence demonstrating the effect of
O
Third, O
Effects of Diabetes on Signaling Pathways That Modulate Renal Activity and/or Expression of NOS
In vitro evidence has demonstrated that eNOS is regulated by coordinated signaling via phosphorylation and dephosphorylation of tyrosine, serine, and threonine amino acid residues (32). For example, phosphorylation of Ser1177/1179 leads to activation of the enzyme (42), whereas phosphorylation of Thr495 has an opposite effect (33). Diabetes, by altering various signaling pathways, may theoretically influence the phosphorylation status of eNOS and presumably also of other NOS isoenzymes.The impact of PKC activation in the pathophysiology of nephropathy has
been well established (70). Phosphorylation of eNOS by PKC
inhibits its catalytic activity (47), and this
inhibition is accomplished by phosphorylation of Thr495 and
dephosphorylation of Ser1177 (82). Specifically, the
PKC- isoform has been implicated in the pathophysiology of
complications (69). This isoform inactivates eNOS in
endothelial cells and microvessels of insulin-resistant Zucker rats
(75). Identification of the link between PKC and eNOS
activity provides strong support for the concept of NO insufficiency in
the diabetic kidney (Fig. 1).
|
More recently, other signaling pathways have been identified as
modulators of NOS activity along with evidence suggesting alterations
of these pathways in diabetes. Akt kinase (PKB), a downstream effector
of phosphatidylinositol 3-kinase, has been identified as the kinase
responsible for Ca2+-independent activation of eNOS
(29, 34). Akt activates eNOS by Ser1177/1179
phosphorylation. This kinase has been implicated in cellular signaling
of factors relevant to diabetic complications, such as insulin
(162, 163), VEGF (34), ANG II (38, 121, 134), leptin (140, 152), TGF- (17),
and shear stress (42) (Fig. 1). Recently, Feliers et al.
(31) demonstrated an increase in Akt expression and
activity in the renal cortex of db/db mice, a genetic model
of type 2 diabetes.
We have repeatedly emphasized the presence or absence of insulin treatment preventing severe hyperglycemia as a possible contributor to disparate findings in a number of the preceding studies. In our opinion, the crucial role of exogenous insulin is not merely in modulating blood glucose levels but also in its ability to influence NO synthesis. Indeed, early after induction of diabetes, residual secretion of insulin may be sufficient to achieve moderate hyperglycemia. However, to achieve given levels of blood glucose, the amount of exogenous insulin could be substantially greater compared with the amount of endogenously secreted hormone. Thus, acting via Akt, insulin could be an independent activator of eNOS in various tissues including the kidney. This pathway would not be reflected, for example, in studies using stimulation with ACh, a widely accepted approach for testing eNOS function. We cannot exclude that impaired agonist-induced NO production, as observed in a number of studies, could be counterbalanced by alternative signaling pathways, such as Akt. Local activation of Akt by hyperinsulinemia may be an example of such a situation (Fig. 1).
Some investigators have suggested a defect in Akt signaling as one of
the sites of insulin resistance (18, 73), a hallmark feature of type 2 diabetes. An important issue is whether resistance to
metabolic actions of insulin affects not only metabolic but also
vasoactive or renal actions of the hormone. An increase in Akt
expression in the kidney in insulin-resistant mice suggests that these
two processes may be separated (31). However, opposite evidence suggesting resistance to insulin-induced NOS activation also
exists (75). Furthermore, another line of in vitro
evidence suggests that in high glucose, the Akt-dependent
phosphorylation site responsible for eNOS activation can be modified by
N-acetyl glucosamine (30), in a process linked
to mitochondrial O
Unlike eNOS, there is much less evidence on the effects of insulin and diabetes-induced signaling pathways on nNOS activity. However, there is indirect evidence from other tissues suggesting that insulin could activate nNOS. For example, pial arteriolar vasodilation associated with insulin-induced hypoglycemia is mediated by nNOS-derived NO (106). Similar to eNOS, rat nNOS contains an Akt-dependent phosphorylation motif (34). However, phosphorylation of this motif has not been shown to significantly modulate NO production by the enzyme (34).
Although cellular signaling pathways possibly modulating nNOS activity in the diabetic kidney have not been elucidated, other mechanisms involved in renal nNOS regulation have been identified. Importantly, some of these mechanisms may be active in the diabetic kidney. Under physiological conditions, sodium delivery to the distal tubule is the major acute determinant of nNOS activity in the MD cells (51, 149). However, based on micropuncture studies by Vallon et al. (135) showing a decrease in solute content in early distal tubular fluid in diabetic rats, stimulation of nNOS by increased solute delivery to the MD in diabetes is unlikely. Welch and Wilcox (147) reported that blunting of TGF responses by NO could be limited by L-Arg availability in the tubular lumen and by its uptake via the y+ transport system. To our knowledge, the availability of L-Arg in diabetic compared with normal kidneys remains unknown. Indirect clues that could help elucidate this issue are rather conflicting. Plasma L-Arg levels are decreased in diabetes (100), but urinary L-Arg excretion has been reported to be markedly increased (103). Renal nNOS is chronically activated in parallel with the renin-angiotensin system (RAS) in such pathophysiological states as two-kidney, one-clip hypertension, furosemide treatment, or dietary sodium restriction (12). Assuming that a low-sodium diet decreases distal sodium delivery, this mechanism corresponds to the situation in the distal tubule as described by Vallon et al. (135) in diabetic rats and thus represents a possible pathway resulting in activation of nNOS.
![]() |
NO AND RENAL STRUCTURAL CHANGES IN DIABETES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the diabetic kidney, most cells undergo hypertrophy. This
process, together with accumulation of extracellular matrix, underlies
renal structural changes in diabetes that are characterized by
mesangial expansion (93), later development of
glomerulosclerosis, and by tubular hypertrophy and later interstitial
fibrosis (36). Data reported by several groups have
provided evidence that this hypertrophy is, at least in part,
attributable to altered cell cycle regulation. This complex process,
reviewed elsewhere (151), is associated with increased
expression of cyclin-dependent kinase (CDK) inhibitors, such as
p21Cip1 and p27Kip1 (74, 153),
resulting in G1-phase arrest (151). These
molecules can be induced by glucose and other mediators of the diabetic milieu, such as glucose-TGF- or RAS-TGF-
pathways
(151), molecules whose importance in the pathophysiology
of diabetic nephropathy is well documented (2).
Antiproliferative actions of NO on mesangial cells or vascular smooth
muscle cells, and its tendency to shift cells into the hypertrophic
phenotype, have been recognized for over a decade (35, 57,
144). Later studies have provided evidence for mechanisms responsible for these actions (41, 53, 114, 122). NO
directly modulates smooth muscle cell cycle progression by upregulation of p21Cip1 and inhibition of cyclin-dependent kinase 2 activity. Thus it appears that NO growth actions in the kidney display
substantial similarities to the diabetic milieu. Importantly, these
effects of NO are independent of cGMP generation (122).
Furthermore, TGF- can induce eNOS in vitro (52) as well
as in vivo in both diabetic (94) and nondiabetic tissues
(101, 158). TGF-
-induced activation of eNOS may involve
Akt kinase signaling (17, 94) (Fig. 1).
Another factor implicated in the pathogenesis of diabetic nephropathy and signaling via Akt is VEGF (27). Reviewing the data on VEGF well illustrates the controversial nature of evidence discussed in this review. There is abundant evidence suggesting NO as a mediator of VEGF actions (44, 48, 136) (Fig. 1). However, some actions of VEGF presumably mediated by NO, such as endothelial proliferation (87), are not typically observed in the diabetic kidney and are not in accordance with the effects of NO on cellular trophic status discussed above. In contrast, other effects, such as local NO-dependent increases in vascular permeability, vasodilation, or glomerular hypertrophy, are well consistent with diabetic renal pathophysiology (27, 126). In any case, provided that the hypothesis about the role of VEGF is valid, it is hard to reconcile with those findings suggesting a NO deficit in the diabetic kidney.
As with other issues discussed in this review, convincing contradictory
evidence has also been reported in this area, suggesting that a NO
deficit may underlie the development of renal structural changes in
diabetes. Several in vitro reports have indicated that NO can interfere
with pathways, resulting in TGF- induction by high glucose or other
mechanisms active in the diabetic kidney (24, 117). It has
recently been reported that TGF-
suppression by NO in mesangial
cells cultured in high glucose is mediated by downregulation of
thrombospondin-1 (145). This view was further supported by
observations that the RAS-TGF-
axis is involved in mediating organ
injury during chronic NOS inhibition in diabetic (21) and
nondiabetic models (59, 129). Thus mechanisms discussed in
this section suggest that both increased as well as decreased renal NO
activity may result in characteristic changes in diabetic renal morphology.
![]() |
SUMMARY |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We have reviewed a wide spectrum of findings and issues that have amassed concerning the pathophysiology of the renal NO system in diabetes. It is apparent that it might be practically impossible to reconcile such complex and controversial evidence and find a unifying scenario characterizing these processes. However, we believe that some patterns are emerging. One of major general controversies exists between the in vitro findings, which generally suggest decreased bioavailability of NO in the diabetic kidney, and in vivo observations, which tend to suggest enhanced renal NO production and/or activity in diabetes, at least in the early stages. We believe that the diabetic milieu is complex and that in vitro approaches may miss some important mechanisms that comodulate NO activity in a particular system. On the other hand, these studies are indispensable in the identification of precise mechanisms resulting in alterations of the NO system in diabetes. Most importantly, in vitro studies describe processes whereby high glucose levels, a hallmark metabolic feature of diabetes, exert deleterious effects on NO bioavailability.
There is little doubt that severe diabetes with profound insulinopenia can be viewed as a state of general NO deficiency, including in the kidney. However, it is important to note that we focus our hypotheses and conclusions on the events occurring during moderate glycemic control, with some degree of treatment with exogenous insulin (Fig. 1). This situation represents more the clinically applicable model most closely resembling the situation in patients destined for development of nephropathy.
Diabetes triggers mechanisms that in parallel enhance and suppress NO bioavailability in the kidney (Fig. 1). We hypothesize that during the early phases of nephropathy, the balance between these two opposing forces is shifted toward NO. This plays a role in the development of characteristic hemodynamic changes and may contribute to consequent structural alterations in glomeruli. Both eNOS and nNOS can contribute to altered NO production. These enzymes, in particular eNOS, can be activated by Ca2+-independent and alternative routes of activation that may be elusive in traditional methods of investigation. As the duration of exposure to the diabetic milieu increases, factors that suppress NO bioavailability gradually prevail. Increasing accumulation of AGE may be one of the culprits in this process. In addition, this balance is continuously modified by actual metabolic control and the degree of insulinopenia.
Alterations of the NO system in the diabetic kidney and their role in the pathophysiology of diabetic nephropathy still represent a great challenge for future research. There are a number of topics in this area that warrant further investigation. Future investigations in this area may focus on, among other topics, direct in vivo measurements of NO production in different compartments of the diabetic kidney and their changes in response to various stimuli; the biochemistry of eNOS and nNOS with respect to the changes in quaternary structure and cellular localization and posttranslational changes; and activity of signaling pathways, leading to modulation of NOS activities, as well as on possible alterations in NO signaling. Considering the epidemic increase in type 2 diabetes-associated nephropathy, studies should focus on evaluating these systems in models of type 2 diabetes.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported, in part, by National Institute on Aging Grant AG-14699, the American Diabetes Association, and the Juvenile Diabetes Research Foundation. R. Komers is also supported by Grant VZ/CEZ L17/98:00023001 from the Ministry of Healthcare, Czech Republic.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: R. Komers, Div. of Nephrology and Hypertension, Oregon Health and Science Univ., PP262, 3314 SW US Veterans Hospital Rd., Portland, OR 97201-2940 (E-mail: komersr{at}ohsu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajprenal.00265.2002
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ahn, KY,
Mohaupt MG,
Madsen KM,
and
Kone BC.
In situ hybridization localization of mRNA encoding inducible nitric oxide synthase in rat kidney.
Am J Physiol Renal Fluid Electrolyte Physiol
267:
F748-F757,
1994
2.
Al-Douahji, M,
Brugarolas J,
Brown PA,
Stehman-Breen CO,
Alpers CE,
and
Shankland SJ.
The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy.
Kidney Int
56:
1691-1699,
1999[ISI][Medline].
3.
Alabadi, JA,
Miranda FJ,
Llorens S,
Ruiz de Apodaca RF,
Centeno JM,
and
Alborch E.
Diabetes potentiates acetylcholine-induced relaxation in rabbit renal arteries.
Eur J Pharmacol
415:
225-232,
2001[ISI][Medline].
4.
Alberola, A,
Pinilla JM,
Quesada T,
Romero JC,
Salom MG,
and
Salazar FJ.
Role of nitric oxide in mediating renal response to volume expansion.
Hypertension
9:
780-784,
1992.
5.
Anderson, S,
and
Komers R.
Pathogenesis of diabetic glomerulopathy: the role of glomerular hemodynamic factors.
In: The Kidney and Hypertension in Diabetes Mellitus, edited by Mogensen CE.. Boston, MA: Kluwer, 2000, p. 281-294.
6.
Arima, S,
Ito S,
Omata K,
Takeuchi K,
and
Abe K.
High glucose augments angiotensin II action by inhibiting NO synthesis in in vitro microperfused rabbit afferent arterioles.
Kidney Int
48:
683-689,
1995[ISI][Medline].
7.
Bachmann, S,
Bosse HM,
and
Mundel P.
Topography of nitric oxide synthesis by localizing constitutive NO synthases in mammalian kidney.
Am J Physiol Renal Fluid Electrolyte Physiol
268:
F885-F898,
1995
8.
Bank, N,
and
Aynedjian HS.
Role of EDRF (nitric oxide) in diabetic renal hyperfiltration.
Kidney Int
43:
1306-1312,
1993[ISI][Medline].
9.
Baylis, C,
and
Qiu C.
Importance of nitric oxide in the control of renal hemodynamics.
Kidney Int
49:
1727-1731,
1996[ISI][Medline].
10.
Beenen, OH,
Mathy MJ,
Pfaffendorf M,
and
van Zwieten PA.
Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.
J Hypertens
14:
1125-1130,
1996[ISI][Medline].
11.
Bhardwaj, R,
and
Moore PK.
Increased vasodilator response to acetylcholine of renal blood vessels from diabetic rats.
J Pharm Pharmacol
40:
739-742,
1988[ISI][Medline].
12.
Bosse, HM,
Bohm R,
Resch S,
and
Bachmann S.
Parallel regulation of constitutive NO synthase and renin at JGA of rat kidney under various stimuli.
Am J Physiol Renal Fluid Electrolyte Physiol
269:
F793-F805,
1995
13.
Brodsky, SV,
Morrishow AM,
Dharia N,
Gross SS,
and
Goligorsky MS.
Glucose scavenging of nitric oxide.
Am J Physiol Renal Physiol
280:
F480-F486,
2001
14.
Bucala, R,
Tracey KJ,
and
Cerami A.
Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.
J Clin Invest
87:
432-438,
1991[ISI][Medline].
15.
Carmines, PK,
Fallet RW,
Roscow J,
Sasser JM,
and
Pollock JS.
Renal cortical Hsp90 and its impact on NOS activity and afferent arteriolar tone are diminished in diabetes mellitus (Abstract).
J Am Soc Nephrol
13:
532A,
2002.
16.
Carmines, PK,
Ohishi K,
and
Ikenaga H.
Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus.
J Clin Invest
98:
2564-2571,
1996
17.
Chen, H,
Li D,
Saldeen T,
and
Mehta JL.
TGF-1 modulates NOS expression and phosphorylation of Akt/PKB in rat myocytes exposed to hypoxia-reoxygenation.
Am J Physiol Heart Circ Physiol
281:
H1035-H1039,
2001
18.
Cho, H,
Mu J,
Kim JK,
Thorvaldsen JL,
Chu Q,
Crenshaw EB, III,
Kaestner KH,
Bartolomei MS,
Shulman GI,
and
Birnbaum MJ.
Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB ).
Science
292:
1728-1731,
2001
19.
Choi, KC,
Kim NH,
An MR,
Kang DG,
Kim SW,
and
Lee J.
Alterations of intrarenal renin-angiotensin and nitric oxide systems in streptozotocin-induced diabetic rats.
Kidney Int
52, Suppl 60:
S23-S27,
1997[ISI].
20.
Cosentino, F,
Hishikawa K,
Katusic ZS,
and
Luscher TF.
High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells.
Circulation
96:
25-28,
1997
21.
Craven, PA,
DeRubertis FR,
and
Melhem M.
Nitric oxide in diabetic nephropathy.
Kidney Int
52, Suppl 60:
S46-S53,
1997.
22.
Craven, PA,
Studer RK,
and
DeRubertis FR.
Impaired nitric oxide release by glomeruli from diabetic rats.
Metabolism
44:
695-698,
1995[ISI][Medline].
23.
Craven, PA,
Studer RK,
and
DeRubertis FR.
Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated supression of cholinergic response.
J Clin Invest
93:
311-320,
1994[ISI][Medline].
24.
Craven, PA,
Studer RK,
Felder J,
Phillips S,
and
DeRubertis FR.
Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells.
Diabetes
46:
671-681,
1997[Abstract].
25.
Dai, FX,
Diederich A,
Skopec J,
and
Diederich D.
Diabetes-induced endothelial dysfunction in streptozotocin-treated rats: role of prostaglandin endoperoxides and free radicals.
J Am Soc Nephrol
4:
1327-1336,
1993[Abstract].
26.
De Vriese, AS,
Stoenoiu MS,
Elger M,
Devuyst O,
Vanholder R,
Kriz W,
and
Lameire NH.
Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide.
Kidney Int
60:
202-210,
2001[ISI][Medline].
27.
De Vriese, AS,
Tilton RG,
Elger M,
Stephan CC,
Kriz W,
and
Lameire NH.
Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.
J Am Soc Nephrol
12:
993-1000,
2001
28.
Deng, A,
and
Baylis C.
Locally produced EDRF controls preglomerular resistance and ultrafiltration coefficient.
Am J Physiol Renal Fluid Electrolyte Physiol
264:
F212-F215,
1993
29.
Dimmeler, S,
Fleming I,
Fisslthaler B,
Hermann C,
Busse R,
and
Zeiher AM.
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.
Nature
399:
601-605,
1999[ISI][Medline].
30.
Du, XL,
Edelstein D,
Dimmeler S,
Ju Q,
Sui C,
and
Brownlee M.
Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site.
J Clin Invest
108:
1341-1348,
2001
31.
Feliers, D,
Duraisamy S,
Faulkner JL,
Duch J,
Lee AV,
Abboud HE,
Choudhury GG,
and
Kasinath BS.
Activation of renal signaling pathways in db/db mice with type 2 diabetes.
Kidney Int
60:
495-504,
2001[ISI][Medline].
32.
Fleming, I,
Bauersachs J,
Fisslthaler B,
and
Busse R.
Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress.
Circ Res
82:
686-695,
1998
33.
Fleming, I,
Fisslthaler B,
Dimmeler S,
Kemp BE,
and
Busse R.
Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity.
Circ Res
88:
E68-E75,
2001[ISI][Medline].
34.
Fulton, D,
Gratton JP,
McCabe TJ,
Fontana J,
Fujio Y,
Walsh K,
Franke TF,
Papapetropoulos A,
and
Sessa WC.
Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.
Nature
399:
597-601,
1999[ISI][Medline].
35.
Garg, UC,
and
Hassid A.
Inhibition of rat mesangial cell mitogenesis by nitric oxide generating vasodilators.
Am J Physiol Renal Fluid Electrolyte Physiol
257:
F60-F66,
1989
36.
Gilbert, RE,
and
Cooper ME.
The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?
Kidney Int
56:
1627-1637,
1999[ISI][Medline].
37.
Goor, Y,
Peer G,
Iaina A,
Blum M,
Wollman Y,
Chernihovsky T,
Silverberg D,
and
Cabili S.
Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats.
Diabetologia
39:
1036-1040,
1996[ISI][Medline].
38.
Gorin, Y,
Kim NH,
Feliers D,
Bhandari B,
Choudhury GG,
and
Abboud HE.
Angiotensin II activates Akt/protein kinase B by an arachidonic acid/redox-dependent pathway and independent of phosphoinositide 3-kinase.
FASEB J
15:
1909-1920,
2001
39.
Govers, R,
and
Rabelink TJ.
Cellular regulation of endothelial nitric oxide synthase.
Am J Physiol Renal Physiol
280:
F193-F206,
2001
40.
Griendling, KK,
and
Ushio-Fukai M.
Reactive oxygen species as mediators of angiotensin II signaling.
Regul Pept
91:
21-27,
2000[ISI][Medline].
41.
Guo, K,
Andres V,
and
Walsh K.
Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells.
Circulation
97:
2066-2072,
1998
42.
Harris, MB,
Ju H,
Venema VJ,
Liang H,
Zou R,
Michell BJ,
Chen ZP,
Kemp BE,
and
Venema RC.
Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation.
J Biol Chem
276:
16587-16591,
2001
43.
Hayashi, K,
Loutzenhiser R,
Epstein M,
Suzuki H,
and
Saruta T.
Multiple factors contribute to acetylcholine-induced renal afferent arteriolar vasodilation during myogenic and norepinephrine- and KCl-induced vasoconstriction. Studies in the isolated perfused hydronephrotic kidney.
Circ Res
75:
821-828,
1994[Abstract].
44.
He, H,
Venema VJ,
Gu X,
Venema RC,
Marrero MB,
and
Caldwell RB.
Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src.
J Biol Chem
274:
25130-25135,
1999
45.
Hellermann, GR,
and
Solomonson LP.
Calmodulin promotes dimerization of the oxygenase domain of human endothelial nitric-oxide synthase.
J Biol Chem
272:
12030-12034,
1997
46.
Hink, U,
Li H,
Mollnau H,
Oelze M,
Matheis E,
Hartmann M,
Skatchkov M,
Thaiss F,
Stahl RA,
Warnholtz A,
Meinertz T,
Griendling K,
Harrison DG,
Forstermann U,
and
Munzel T.
Mechanisms underlying endothelial dysfunction in diabetes mellitus.
Circ Res
88:
E14-E22,
2001[ISI][Medline].
47.
Hirata, K,
Kuroda R,
Sakoda T,
Katayama M,
Inoue N,
Suematsu M,
Kawashima S,
and
Yokoyama M.
Inhibition of endothelial nitric oxide synthase activity by protein kinase C.
Hypertension
25:
180-185,
1995
48.
Horowitz, JR,
Rivard A,
van der Zee R,
Hariawala M,
Sheriff DD,
Esakof DD,
Chaudhry GM,
Symes JF,
and
Isner JM.
Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium.
Arterioscler Thromb Vasc Biol
17:
2793-2800,
1997
49.
Hostetter, TH,
Rennke HG,
and
Brenner BM.
The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies.
Am J Med
80:
443-453,
1982.
50.
Hostetter, TH,
Troy JL,
and
Brenner BM.
Glomerular hemodynamics in experimental diabetes mellitus.
Kidney Int
19:
410-415,
1981[ISI][Medline].
51.
Ichihara, A,
Inscho EW,
Imig JD,
and
Navar LG.
Neuronal nitric oxide synthase modulates rat renal microvacular function.
Am J Physiol Renal Physiol
274:
F516-F524,
1998
52.
Inoue, N,
Venema RC,
Sayegh HS,
Ohara Y,
Murphy TJ,
and
Harrison DG.
Molecular regulation of the bovine endothelial cell nitric oxide synthase by transforming growth factor-beta 1.
Arterioscler Thromb Vasc Biol
15:
1255-1261,
1995
53.
Ishida, A,
Sasaguri T,
Kosaka C,
Nojima H,
and
Ogata J.
Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells.
J Biol Chem
272:
10050-10057,
1997
54.
Ishii, N,
Patel KP,
Lane PH,
Taylor T,
Bian K,
Murad F,
Pollock JS,
and
Carmines PK.
Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus.
J Am Soc Nephrol
12:
1630-1639,
2001
55.
Ito, A,
Uriu K,
Inada Y,
Qie YL,
Takagi I,
Ikeda M,
Hashimoto O,
Suzuka K,
Eto S,
Tanaka Y,
and
Kaizu K.
Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat.
J Lab Clin Med
138:
177-185,
2001[ISI][Medline].
56.
Jaimes, EA,
Sweeney C,
and
Raij L.
Effects of the reactive oxygen species hydrogen peroxide and hypochlorite on endothelial nitric oxide production.
Hypertension
38:
877-883,
2001
57.
Janssens, S,
Flaherty D,
Nong Z,
Varenne O,
van Pelt N,
Haustermans C,
Zoldhelyi P,
Gerard R,
and
Collen D.
Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats.
Circulation
97:
1274-1281,
1998
58.
Ju, H,
Zou R,
Venema VJ,
and
Venema RC.
Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity.
J Biol Chem
272:
18522-18525,
1997
59.
Kashiwagi, M,
Shinozaki M,
Hirakata H,
Tamaki K,
Hirano T,
Tokumoto M,
Goto H,
Okuda S,
and
Fujishima M.
Locally activated renin-angiotensin system associated with TGF-1 as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats.
J Am Soc Nephrol
11:
616-624,
2000
60.
Keynan, S,
Hirshberg B,
Levin-Iaina N,
Wexler ID,
Dahan R,
Reinhartz E,
Ovadia H,
Wollman Y,
Chernihovskey T,
Iaina A,
and
Raz I.
Renal nitric oxide production during the early phase of experimental diabetes mellitus.
Kidney Int
58:
740-747,
2000[ISI][Medline].
61.
Kiff, RJ,
Gardiner SM,
Compton AM,
and
Bennett T.
The effects of endothelin-1 and NG-nitro-L-arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin-induced diabetes mellitus.
Br J Pharmacol
103:
1321-1326,
1991[Abstract].
62.
King, AJ,
Zayas MA,
Troy JL,
Downes SJ,
and
Brenner BM.
Inhibition of diabetes-induced hyperfiltration and hyperemia by N-monomethyl-L-arginine (L-NMMA) (Abstract).
J Am Soc Nephrol
1:
666,
1990.
63.
Komers, R,
Allen TJ,
and
Cooper ME.
Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes.
Diabetes
43:
1190-1197,
1994[Abstract].
64.
Komers, R,
Lindsley JN,
Oyama TT,
Allison KM,
and
Anderson S.
Role of neuronal NOS (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes.
Am J Physiol Renal Physiol
279:
F573-F583,
2000
65.
Komers, R,
Lindsley JN,
Oyama TT,
and
Anderson S.
Functional expression of endothelial nitric oxide synthase and caveolin-1 in diabetic kidney cortex (Abstract).
J Am Soc Nephrol
13:
532A,
2002.
66.
Komers, R,
Oyama TT,
Chapman JG,
Allison KM,
and
Anderson S.
Effects of systemic inhibition of neuronal nitric oxide synthase in diabetic rats.
Hypertension
34:
655-661,
2000[ISI].
67.
Komers, R,
Oyama TT,
Lindsley JN,
and
Anderson S.
Long-term inhibition of neuronal nitric oxide (NO) synthase (NOS1) postpones development of proteinuria in uninephrectomized diabetic rats (Abstract).
J Am Soc Nephrol
12:
A4391,
2001.
68.
Kone, BC,
and
Baylis C.
Biosynthesis and homeostatic roles of nitric oxide in the normal kidney.
Am J Physiol Renal Physiol
272:
F561-F578,
1997
69.
Koya, D,
Jirousek MR,
Lin YW,
Ishii H,
Kuboki K,
and
King GL.
Characterization of protein kinase C- isoform activation on the gene expression of transforming factor-
, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats.
J Clin Invest
100:
115-126,
1997
70.
Koya, D,
and
King GL.
Protein kinase C activation and the development of diabetic complications.
Diabetes
47:
859-866,
1998[Abstract].
71.
Koya, D,
Lee IK,
Ishii H,
Kanoh H,
and
King GL.
Prevention of glomerular dysfunction in diabetic rats by treatment with D--tocopherol.
J Am Soc Nephrol
8:
426-435,
1997[Abstract].
72.
Krishna, MC,
Samuni A,
Taira J,
Goldstein S,
Mitchell JB,
and
Russo A.
Stimulation by nitroxides of catalase-like activity of hemeproteins. Kinetics and mechanism.
J Biol Chem
271:
26018-26025,
1996
73.
Krook, A,
Roth RA,
Jiang XJ,
Zierath JR,
and
Wallberg-Henriksson H.
Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects.
Diabetes
47:
1281-1286,
1998[Abstract].
74.
Kuan, CJ,
al-Douahji M,
and
Shankland SJ.
The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy.
J Am Soc Nephrol
9:
986-993,
1998[Abstract].
75.
Kuboki, K,
Jiang ZY,
Takahara N,
Ha SW,
Igarashi M,
Yamauchi T,
Feener EP,
Herbert TP,
Rhodes CJ,
and
King GL.
Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin.
Circulation
101:
676-681,
2000
76.
Malinski, T,
Taha Z,
Grunfeld S,
Patton S,
Kapturczak M,
and
Tomboulian P.
Diffusion of nitric oxide in the aorta wall monitored in situ by porphyrinic microsensors.
Biochem Biophys Res Commun
193:
1076-1082,
1993[ISI][Medline].
77.
Marletta, MA.
Nitric oxide: biosynthesis and biological significance.
Trends Pharmacol Sci
158:
348-352,
1989.
78.
Mattar, AL,
Fujihara CK,
Ribeiro MO,
de Nucci G,
and
Zatz R.
Renal effects of acute and chronic nitric oxide inhibition in experimental diabetes.
Nephron
74:
136-143,
1996[ISI][Medline].
79.
Mattson, DL,
Roman RJ,
and
Cowley AW.
Role of nitric oxide in renal papillary blood flow and sodium excretion.
Hypertension
19:
766-769,
1992[Abstract].
80.
Melhem, MF,
Craven PA,
and
Derubertis FR.
Effects of dietary supplementation of -lipoic acid on early glomerular injury in diabetes mellitus.
J Am Soc Nephrol
12:
124-133,
2001
81.
Michel, T,
and
Feron O.
Nitric oxide synthases: which, where, how, and why?
J Clin Invest
100:
2146-2152,
1997
82.
Michell, BJ,
Chen Z,
Tiganis T,
Stapleton D,
Katsis F,
Power DA,
Sim AT,
and
Kemp BE.
Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase.
J Biol Chem
276:
17625-17628,
2001
83.
Mogensen, CE.
Early glomerular hyperfiltration in insulin-dependent diabetics and late nephropathy.
Scand J Clin Invest
1986:
201-206,
1986.
84.
Mohaupt, MG,
Elzie JL,
Ahn KY,
Clapp WL,
Wilcox CS,
and
Kone BC.
Differential expression and induction of mRNAs encoding two inducible nitric oxide synthases in rat kidney.
Kidney Int
46:
653-665,
1994[ISI][Medline].
85.
Moncada, S,
and
Higgs EA.
The L-arginine-nitric oxide pathway.
N Engl J Med
329:
2002-2012,
1993
86.
Moore, LC,
Thorup C,
Ellinger A,
Paccione J,
Casellas D,
and
Kaskel FJ.
Advanced glycosylation end-products and NO-dependent vasodilation in renal afferent arterioles from diabetic rats.
Acta Physiol Scand
168:
101-106,
2000[ISI][Medline].
87.
Morbidelli, L,
Chang CH,
Douglas JG,
Granger HJ,
Ledda F,
and
Ziche M.
Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium.
Am J Physiol Heart Circ Physiol
270:
H411-H415,
1996
88.
Morrisey, JJ,
McCracken R,
Kaneto H,
Vehaskari M,
Montani D,
and
Klahr S.
Location of an inducible nitric oxide synthase mRNA in the normal kidney.
Kidney Int
45:
998-1005,
1994[ISI][Medline].
89.
Narayanan, K,
Spack L,
McMillan K,
Kilbourn RG,
Hayward MA,
Masters BSS,
and
Griffith OW.
Salkyl-L-thiocitrullines.
J Biol Chem
270:
11103-11110,
1995
90.
Ohishi, K,
and
Carmines PK.
Superoxide dismutase restores the influence of nitric oxide on renal arterioles in diabetes mellitus.
J Am Soc Nephrol
5:
1559-1566,
1995[Abstract].
91.
Omer, S,
Shan J,
Varma DR,
and
Mulay S.
Augmentation of diabetes-associated renal hyperfiltration and nitric oxide production by pregnancy in rats.
J Endocrinol
161:
15-23,
1999
92.
Onozato, ML,
Tojo A,
Goto A,
Fujita T,
and
Wilcox CS.
Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB.
Kidney Int
61:
186-194,
2002[ISI][Medline].
93.
Osterby, R.
Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention.
Diabetologia
35:
803-812,
1992[ISI][Medline].
94.
Oyadomari, S,
Gotoh T,
Aoyagi K,
Araki E,
Shichiri M,
and
Mori M.
Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats.
Nitric Oxide
5:
252-260,
2001[ISI][Medline].
95.
Peterson, TE,
Poppa V,
Ueba H,
Wu A,
Yan C,
and
Berk BC.
Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae.
Circ Res
85:
29-37,
1999
96.
Pflueger, AC,
Larson TS,
Hagl S,
and
Knox F.
Role of nitric oxide in intrarenal hemodynamics in experimental diabetes mellitus in rats.
Am J Physiol Regul Integr Comp Physiol
277:
R725-R733,
1999
97.
Pflueger, AC,
Osswald H,
and
Knox F.
Adenosine-induced renal vasoconstriction in diabetes mellitus.
Am J Physiol Renal Physiol
276:
F340-F346,
1999
98.
Pieper, GM.
Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration.
Diabetologia
42:
204-213,
1999[ISI][Medline].
99.
Pieper, GM.
Review of alterations in endothelial nitric oxide production in diabetes. Protective role of arginine on endothelial dysfunction.
Hypertension
31:
1047-1060,
1998
100.
Pieper, GM,
Jordan M,
Adams MB,
and
Roza AM.
Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes.
Diabetes
33:
1106-1113,
1995.
101.
Poppa, V,
Miyashiro JK,
Corson MA,
and
Berk BC.
Endothelial NO synthase is increased in regenerating endothelium after denuding injury of the rat aorta.
Arterioscler Thromb Vasc Biol
18:
1312-1321,
1998
102.
Pou, S,
Pou WS,
Bredt DS,
Snyder SH,
and
Rosen GM.
Generation of superoxide by purified brain nitric oxide synthase.
J Biol Chem
267:
24173-24176,
1992
103.
Reyes, AA,
Karl IE,
Kissane J,
and
Klahr S.
L-arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats.
J Am Soc Nephrol
4:
1039-1045,
1993[Abstract].
104.
Roczniak, A,
Zimpelmann J,
and
Burns KD.
Effect of dietary salt on neuronal nitric oxide synthase in inner medullary collecting duct.
Am J Physiol Renal Physiol
275:
F46-F54,
1998
105.
Rudberg, S,
Persson B,
and
Dahlquist G.
Increased glomerular filtration rate as a predictor of diabetic nephropathy-an 8-year prospective study.
Kidney Int
41:
822-828,
1992[ISI][Medline].
106.
Santizo, RA,
Koenig HM,
and
Pelligrino DA.
-Adrenoceptor and nNOS-derived NO interactions modulate hypoglycemic pial arteriolar dilation in rats.
Am J Physiol Heart Circ Physiol
280:
H562-H568,
2001
107.
Schini-Kerth, VB,
and
Vanhoutte PM.
Nitric oxide synthases in vascular cells.
Exp Physiol
80:
885-905,
1995[ISI][Medline].
108.
Schnackenberg, CG.
Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature.
Am J Physiol Regul Integr Comp Physiol
282:
R335-R342,
2002
109.
Schnackenberg, CG,
and
Wilcox CS.
The SOD mimetic tempol restores vasodilation in afferent arterioles of experimental diabetes.
Kidney Int
59:
1859-1864,
2001[ISI][Medline].
110.
Scholey, JW,
and
Meyer TW.
Control of glomerular hypertension by insulin administration in diabetic rats.
J Clin Invest
83:
1384-1389,
1989[ISI][Medline].
111.
Schoonmaker, GC,
Fallet RW,
and
Carmines PK.
Superoxide anion curbs nitric oxide modulation of afferent arteriolar ANG II responsiveness in diabetes mellitus.
Am J Physiol Renal Physiol
278:
F302-F309,
2000
112.
Schwartz, D,
Schwartz IF,
and
Blantz RC.
An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats.
J Lab Clin Med
137:
107-114,
2001[ISI][Medline].
113.
Sharma, K,
Danoff TM,
DePiero A,
and
Ziyadeh FN.
Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C.
Biochem Biophys Res Commun
207:
80-88,
1995[ISI][Medline].
114.
Sharma, RV,
Tan E,
Fang S,
Gurjar MV,
and
Bhalla RC.
NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells.
Am J Physiol Heart Circ Physiol
276:
H1450-H1459,
1999
115.
Shin, SJ,
Lai FJ,
Wen JD,
Hsiao PJ,
Hsieh MC,
Tzeng TF,
Chen HC,
Guh JY,
and
Tsai JH.
Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney.
Diabetologia
43:
649-659,
2000[ISI][Medline].
116.
Soulis, T,
Cooper ME,
Sastra S,
Thallas V,
Panagiotopoulos S,
Bjerrum OJ,
and
Jerums G.
Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats.
Diabetologia
40:
1141-1151,
1997[Medline].
117.
Studer, RK,
DeRubertis FR,
and
Craven PA.
Nitric oxide suppresses increases in mesangial cell protein kinase C, transforming growth factor beta, and fibronectin synthesis induced by thromboxane.
J Am Soc Nephrol
7:
999-1005,
1996[Abstract].
118.
Sugimoto, H,
Shikata K,
Matsuda M,
Kushiro M,
Hayashi Y,
Hiragushi K,
Wada J,
and
Makino H.
Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.
Diabetologia
41:
1426-1434,
1998[ISI][Medline].
119.
Sugimoto, H,
Shikata K,
Wada J,
Horiuchi S,
and
Makino H.
Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli.
Diabetologia
42:
878-886,
1999[ISI][Medline].
120.
Suto, T,
Losonczy G,
Qiu C,
Hill C,
Samsell L,
Ruby J,
Charon N,
Venuto R,
and
Baylis C.
Acute changes in urinary excretion of nitrite + nitrate do not necessarily predict renal vascular NO production.
Kidney Int
48:
1272-1277,
1995[ISI][Medline].
121.
Takahashi, T,
Taniguchi T,
Konishi H,
Kikkawa U,
Ishikawa Y,
and
Yokoyama M.
Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells.
Am J Physiol Heart Circ Physiol
276:
H1927-H1934,
1999
122.
Tanner, FC,
Meier P,
Greutert H,
Champion C,
Nabel EG,
and
Luscher TF.
Nitric oxide modulates expression of cell cycle regulatory proteins: a cytostatic strategy for inhibition of human vascular smooth muscle cell proliferation.
Circulation
101:
1982-1989,
2000
123.
Terada, Y,
Tomita K,
Nonoguchi H,
and
Marumo F.
Polymerase chain reaction localization of constitutive nitric oxide synthase and soluble guanylate cyclase messenger RNAs in microdissected rat nephron segments.
J Clin Invest
90:
659-665,
1992[ISI][Medline].
124.
Thorup, C,
Erik A,
and
Persson G.
Macula densa derived nitric oxide in regulation of glomerular capillary pressure.
Kidney Int
49:
430-436,
1996[ISI][Medline].
125.
Thuraisingham, RC,
Nott CA,
Dodd SM,
and
Yaqoob MM.
Increased nitrotyrosine staining in kidneys from patients with diabetic nephropathy.
Kidney Int
57:
1968-1972,
2000[ISI][Medline].
126.
Tilton, RG,
Kawamura T,
Chang KC,
Ido Y,
Bjercke RJ,
Stephan CC,
Brock TA,
and
Williamson JR.
Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.
J Clin Invest
99:
2192-2202,
1997
127.
Tojo, A,
Gross SS,
Zhang L,
Tisher CC,
Schmidt HHHW,
Wilcox CS,
and
Madsen KM.
Immunohistochemical localization of distinct isoforms of nitric oxide synthase in the juxtaglomerular apparatus of normal rat kidney.
J Am Soc Nephrol
4:
1438-1447,
1994[Abstract].
128.
Tolins, JP,
Shultz PJ,
Raij L,
Brown DM,
and
Mauer SM.
Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO.
Am J Physiol Renal Fluid Electrolyte Physiol
265:
F886-F895,
1993
129.
Tomita, H,
Egashira K,
Ohara Y,
Takemoto M,
Koyanagi M,
Katoh M,
Yamamoto H,
Tamaki K,
Shimokawa H,
and
Takeshita A.
Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats.
Hypertension
32:
273-279,
1998
130.
Torffvit, O,
and
Edvinsson L.
Blockade of nitric oxide decreases the renal vasodilatory effect of neuropeptide Y in the insulin-treated diabetic rat.
Pflügers Arch
434:
445-450,
1997[ISI][Medline].
131.
Torffvit, O,
and
Edvinsson L.
Relaxing effect of insulin in renal arteries from diabetic rats.
Regul Pept
79:
147-152,
1999[ISI][Medline].
132.
Trachtman H, Futterweit S, and Crimmins DL. High glucose inhibits
nitric oxide production in cultured rat mesangial cells. J
Am Soc Nephrol: 1276-1282, 1997.
133.
Uematsu, M,
Ohara Y,
Navas JP,
Nishida K,
Murphy TJ,
Alexander RW,
Nerem RM,
and
Harrison DG.
Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress.
Am J Physiol Cell Physiol
269:
C1371-C1378,
1995
134.
Ushio-Fukai, M,
Alexander RW,
Akers M,
Yin Q,
Fujio Y,
Walsh K,
and
Griendling KK.
Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells.
J Biol Chem
274:
22699-22704,
1999
135.
Vallon, V,
Blantz RC,
and
Thomson S.
Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats.
Am J Physiol Renal Fluid Electrolyte Physiol
269:
F876-F883,
1995
136.
Van der Zee, R,
Murohara T,
Luo Z,
Zollmann F,
Passeri J,
Lekutat C,
and
Isner JM.
Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium.
Circulation
95:
1030-1037,
1997
137.
Vanhoutte, PM.
Endothelium-derived free radicals: for worse and for better.
J Clin Invest
107:
23-25,
2001
138.
Vasquez-Vivar, J,
Hogg N,
Martasek P,
Karoui H,
Pritchard KA, Jr,
and
Kalyanaraman B.
Tetrahydrobiopterin-dependent inhibition of superoxide generation from neuronal nitric oxide synthase.
J Biol Chem
274:
26736-26742,
1999
139.
Vasquez-Vivar, J,
Kalyanaraman B,
Martasek P,
Hogg N,
Masters BS,
Karoui H,
Tordo P,
and
Pritchard KA, Jr.
Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors.
Proc Natl Acad Sci USA
95:
9220-9225,
1998
140.
Vecchione, C,
Maffei A,
Colella S,
Aretini A,
Poulet R,
Frati G,
Gentile MT,
Fratta L,
Trimarco V,
Trimarco B,
and
Lembo G.
Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway.
Diabetes
51:
168-173,
2002
141.
Veelken, R,
Hilgers KF,
Hartner A,
Haas A,
Bohmer K,
and
Sterzel RB.
Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy.
J Am Soc Nephrol
11:
71-79,
2000
142.
Venema, RC,
Sayegh HS,
Kent JD,
and
Harrison DG.
Identification, characterization, and comparison of calmodulin binding domains of the endothelial and inducible nitric oxide synthases.
J Biol Chem
271:
6435-6440,
1996
143.
Verbeke, P,
Perichon M,
Friguet B,
and
Bakala H.
Inhibition of nitric oxide synthase activity by early and advanced glycation end products in cultured rabbit proximal tubular epithelial cells.
Biochim Biophys Acta
1502:
481-494,
2000[ISI][Medline].
144.
Von der Leyen, HE,
Gibbons GH,
Morishita R,
Lewis NP,
Zhang L,
Nakajima M,
Kaneda Y,
Cooke JP,
and
Dzau VJ.
Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene.
Proc Natl Acad Sci USA
92:
1137-1141,
1995[Abstract].
145.
Wang, S,
Shiva S,
Poczatek MH,
Darley-Usmar V,
and
Murphy-Ullrich JE.
Nitric oxide and cGMP-dependent protein kinase regulation of glucose- mediated thrombospondin1-dependent TGF- activation in mesangial cells.
J Biol Chem
277:
9880-9888,
2002
146.
Wang, YX,
Brooks DP,
and
Edwards RM.
Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats.
Am J Physiol Regul Integr Comp Physiol
264:
R952-R956,
1993
147.
Welch, WJ,
and
Wilcox CS.
Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure.
J Clin Invest
100:
2235-2242,
1997
148.
Wever, RM,
van Dam T,
van Rijn HJ,
de Groot F,
and
Rabelink TJ.
Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase.
Biochem Biophys Res Commun
237:
340-344,
1997[ISI][Medline].
149.
Wilcox, CS,
and
Welch WJ.
Macula densa nitric oxide synthase: expression, regulation, and function.
Kidney Int
54:
S53-S57,
1998[ISI].
150.
Wilcox, CS,
Welch WJ,
Murad F,
Gross SS,
Taylor G,
Levi R,
and
Schmidt HH.
Nitric oxide synthase in macula densa regulates glomerular capillary pressure.
Proc Natl Acad Sci USA
89:
11993-11997,
1992[Abstract].
151.
Wolf, G.
Cell cycle regulation in diabetic nephropathy.
Kidney Int
58, Suppl 77:
S-59-S-66,
2000.
152.
Wolf, G,
Hamann A,
Han DC,
Helmchen U,
Thaiss F,
Ziyadeh FN,
and
Stahl RA.
Leptin stimulates proliferation and TGF- expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.
Kidney Int
56:
860-872,
1999[ISI][Medline].
153.
Wolf, G,
Schroeder R,
Thaiss F,
Ziyadeh FN,
Helmchen U,
and
Stahl RA.
Glomerular expression of p27Kip1 in diabetic db/db mouse: role of hyperglycemia.
Kidney Int
53:
869-879,
1998[ISI][Medline].
154.
Wu, F,
Park F,
Cowley AW,
and
Mattson DL.
Quantification of nitric oxide synthase activity in microdissected segments of the rat kidney.
Am J Physiol Renal Physiol
276:
F874-F881,
1999
155.
Xia, Y,
Tsai AL,
Berka V,
and
Zweier JL.
Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process.
J Biol Chem
273:
25804-25808,
1998
156.
Xia, Y,
and
Zweier JL.
Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages.
Proc Natl Acad Sci USA
94:
6954-6958,
1997
157.
Yagihashi, N,
Nishida N,
Seo HG,
Taniguchi N,
and
Yagihashi S.
Expression of nitric oxide synthase in macula densa in streptozotocin diabetic rats.
Diabetologia
39:
793-799,
1996[ISI][Medline].
158.
Ying, WZ,
and
Sanders PW.
Dietary salt enhances glomerular endothelial nitric oxide synthase through TGF-1.
Am J Physiol Renal Physiol
275:
F18-F24,
1998
159.
Zatz, R,
and
de Nucci G.
Effects of acute nitric oxide inhibition on rat glomerular microcirculation.
Am J Physiol Renal Fluid Electrolyte Physiol
261:
F360-F363,
1991
160.
Zatz, R,
Dunn BR,
Meyer TW,
Anderson S,
Rennke HG,
and
Brenner BM.
Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.
J Clin Invest
77:
1925-1930,
1986[ISI][Medline].
161.
Zatz, R,
Meyer TW,
Rennke HG,
and
Brenner BM.
Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic nephropathy.
Proc Natl Acad Sci USA
82:
5963-5967,
1985[Abstract].
162.
Zeng, G,
Nystrom FH,
Ravichandran LV,
Cong LN,
Kirby M,
Mostowski H,
and
Quon MJ.
Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells.
Circulation
101:
1539-1545,
2000
163.
Zeng, G,
and
Quon MJ.
Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells.
J Clin Invest
98:
894-898,
1996