1 Anatomisches Institut, Charité, Humboldt Universität, 13353 Berlin, Germany; and 2 Department of Pediatric Surgery, Erasmus University, 3000 DR Rotterdam, The Netherlands
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ABSTRACT |
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This study
describes elevated histochemical signals for nitric oxide synthase-1
(NOS1) and cyclooxygenase-2 (COX-2) in juxtaglomerular apparatus (JGA)
and adjacent thick ascending limb of the kidney of fawn-hooded
hypertensive rats (FHH). Two different age groups of FHH (8 and 16 wk;
FHH8 and FHH16, respectively) were compared with genetically related
fawn-hooded rats with normal blood pressure (FHL) that served as
controls. Histopathological changes in FHH comprised focal segmental
glomerulosclerosis (FSGS), focal matrix overexpression, and a moderate
arteriolopathy with hypertrophy of the media, enhanced immunoreactivity
for -smooth muscle actin, and altered distribution of myofibrils.
Macula densa NOS activity, as expressed by NADPH-diaphorase staining,
and NOS1 mRNA abundance were significantly elevated in FHH8 (+153 and
+88%; P < 0.05) and FHH16 (+93 and +98%;
P < 0.05), respectively. Even higher elevations were
registered for COX-2 immunoreactivity in FHH8 (+166%;
P < 0.05) and FHH16 (+157%; P < 0.05). The intensity of renin immunoreactivity and renin mRNA
expression in afferent arterioles was also elevated in FHH8 (+51 and
+166%; P < 0.05) and FHH16 (+105 and +136%;
P < 0.05), respectively. Thus we show that coordinate upregulation of tubular NOS1, COX-2, and renin expression precedes, and
continues after, the manifestation of glomerulosclerotic damage in FHH.
These observations may have implications in understanding the role of
local paracrine mediators in glomerular disease.
juxtaglomerular apparatus; macula densa; nitric oxide; prostaglandins; renin
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INTRODUCTION |
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PATIENTS WITH HYPERTENSION develop end-stage renal failure only to some proportion, and there is increasing evidence that genetic factors also play a role in the susceptibility of hypertension-induced renal failure in individuals with no underlying renal disease (11). This damage can be either hypertension induced or hypertension associated (8). The most compelling evidence for the existence of renal susceptibility genes comes from the fawn-hooded hypertensive rat (FHH), which develops severe glomerulosclerosis and albuminuria in association with arterial hypertension (26, 29, 40). Transplantation studies have shown that the renal damage "travels" with the FHH kidneys, suggesting that it has its origin in the kidney and not in the systemic circulation (23), and two genes, Rf-1 and Rf-2, were determined, which probably contribute substantially to renal damage in FHH in a blood pressure-independent manner (8). Elevations in renal blood flow, glomerular filtration rate (GFR), and glomerular capillary pressure (PGC) precede the development of renal damage in this strain (36, 39). The incidence and severity of the lesions increase with time, positively correlate with plasma renin activity in the late stage, and eventually lead to renal failure at the age of ~1 yr (21). Treatment with antihypertensive agents showed that PGC in FHH is related to arterial pressure (41). Autoregulation of renal blood flow and GFR is impaired in FHH, probably owing to an altered myogenic response of small arteries (40); the resulting glomerular hypertension is thought to be the crucial factor initiating and maintaining the progressive kidney lesions (36, 40). Despite the low afferent arteriolar resistance, tubuloglomerular feedback (TGF) responses were normal in FHH in absolute terms but occurred at a relatively elevated PGC of 55 mmHg, thus indicating that the glomerular vessels fail to normalize pressure (41).
The juxtaglomerular apparatus (JGA) importantly contributes to the control of glomerular arteriolar resistance and renin synthesis/release and may therefore be causally involved in the pathogenetic changes in FHH. Relationships between these parameters and macula densa (MD)-derived paracrine factors believed to mediate tubulovascular signaling have been established (for review, see Refs. 7 and 31).
The constitutive type 1 isoform of nitric oxide synthase (NOS1) located in the MD is likely to release NO to tonically reduce the vasoconstrictory response of TGF (1, 43), and it may also play a role in the control of renin secretion (33). In a similar manner, the inducible form of prostaglandin-synthesizing cyclooxygenase (COX-2) is constitutively expressed in cells of the thick ascending limb (TAL) adjacent to the MD and, to a lesser extent, in MD cells proper (19). Like NOS1, COX-2 appears to be involved in the regulation of glomerular arteriolar tone and renin synthesis (17, 18). Inhibition of COX-2 in progressive renal disease had a renoprotective effect (42). It has further been suggested that COX-2 function is under the control of NO and is negatively regulated by angiotensin II (9, 10). In FHH, increased urinary levels of various eicosanoids have previously been reported to coincide with hyperfiltration (14).
The present study addresses the question as to whether juxtaglomerular activity/expression levels of juxtaglomerular NOS1 and COX-2 are altered in 8- and 16-wk-old FHH compared with fawn-hooded rats with low blood pressure (FHL); FHL served as controls because they share most of the identified genetic loci associated with renal disease susceptibility in FHH but do not develop hypertension and early renal damage (29, 36, 39). Morphological parameters are documented to monitor age-related, specific vascular and glomerular damages and to evaluate their potential relationship to paracrine signals from the JGA.
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MATERIALS AND METHODS |
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Animals. Experiments were performed in 8-wk-old male FHH rats (FHH8; n = 9), in 16-wk-old male FHH rats (FHH16; n = 10), and 16-wk-old male FHL rats (FHL16; n = 9). Rats were bred at the animal facilities of Erasmus University (Rotterdam, The Netherlands). Animals were housed and fed under standard conditions and received tap water ad libitum. Clinical parameters were not evaluated in detail in the groups of the present study, because values (GFR, creatinine clearance, albuminuria, systolic blood pressure, etc.) had been solidly established by our group with rats of identical age that were kept under identical conditions (36, 39). Thus only blood pressure levels and urinary protein concentrations were measured before the death of the animals. Blood pressure was determined by indirect tail-cuff plethysmography in conscious animals. Proteinuria was taken as an indicator of the progression of renal damage. Therefore, urine was collected from individual rats in metabolic cages for 24-h periods. Total urinary protein concentration was measured colorimetrically by precipitation with 3% sulfosalicylic acid.
Perfusion fixation. Animals were anesthetized by using Nembutal. For morphological and histochemical analysis, animals were perfusion-fixed by cannulation of the abdominal aorta by using freshly prepared paraformaldehyde (3% in PBS) at a pressure of 220 mmHg initially, then 60 mmHg (32). To protect the tissues from freezing artifacts, subsequent perfusion was done with a sucrose-PBS solution adjusted to 800 mosmol/kgH2O. Kidneys were then removed and in part immediately shock-frozen in liquid nitrogen-cooled isopentane, in part processed for paraffin embedding, and in part postfixed in 1.5% glutaraldehyde for electron microscopy preparation.
Morphological analysis. For histopathological study and for determination of the extent of glomerular damage, 5-µm-thick paraffin sections were stained with periodic acid-Schiff reagent (PAS). For fine structural morphology, semithin sections (1 µm) from Epon-embedded tissue were cut and stained with Richardson's solution. For transmission electron microscopy, ultrathin sections were contrasted in uranyl acetate and lead citrate. The extent of glomerular damage was determined on two 5-µm-thick PAS-stained paraffin sections/rat; a total of 400-600 glomeruli were evaluated per rat, and at least 4 rats/group were studied. Glomeruli showing significant features of segmental or global sclerosis, i.e., adhesion of the tuft to Bowman's capsule, capillary collapse and/or ballooning, mesangial matrix expansion, and deposition of hyalin material, respectively, were scored. The percent values were taken as the sclerosis index.
Histochemical analysis. For demonstration of NOS tissue activity, NADPH diaphorase (NADPH-d) reaction was performed as described (1). Five-micrometer-thick cryostat sections were incubated in 0.1 M phosphate buffer containing nitro blue tetrazolium (NBT), NADPH, and Triton X-100. Tissues of all groups were processed simultaneously at an incubation temperature of 37°C. Reaction was stopped for all tissues after 30 min when the MD signal was clearly distinguishable and background staining had not yet appeared.
For visualization of mRNA expression, in situ hybridization was performed by using riboprobes transcribed from NOS1-, renin-, andQuantification of histochemical NOS and renin signal. NOS1, COX-2, and renin histochemical signals were semiquantitatively evaluated as described (6). To establish changes in MD, NOS1 enzyme activity, and transcription rate, the mean number of NOS-positive cells per single glomerulus was determined by evaluating a total of 400-600 glomeruli/animal. NOS enzyme activity at the MD was detected by the NADPH-d reaction. Colocalization of NADPH-d and NOS in the same cells has been demonstrated earlier (1). It was assumed that the intensity of the NADPH-d reaction on sections from perfusion-fixed kidneys was proportional to the activity of NOS1 and to the amount of NO released. Using standardized histochemical conditions with constant exposure time and temperature for each experiment, we performed the semiquantitative evaluation under the premise that, under control conditions, not all MD cells are histochemically positive for NADPH-d; instead, a proportion of cells regularly fall below the detection level of a signal. Thus under stimulatory conditions, previously absent NADPH-d signal in some MD cells would shift from below to above the detection limit of the method; conversely, under suppressive conditions a reduction of the number of positive cells below control level could be established. By analogy, NOS1 transcription rate and immunoreactive COX-2 abundance in the MD were estimated. NOS1 mRNA abundance was estimated by counting MD cells with a positive hybridization signal; it was assumed that changes in the number of reactive MD cells were proportional to changes in MD-NOS1 mRNA abundance. To this end, the color reaction after in situ hybridization had to be stopped simultaneously in the experimental groups to be compared. All COX-2-immunoreactive cells of TAL segments in the vicinity of the JGA and of MD were counted to determine changes in the COX-2 protein abundance in FHH compared with FHL. The evaluation of renin expression was based on the well-established fact that, with varying stimuli, a metaplastic transformation occurs between renin-synthesizing cells and typical smooth muscle cells of the afferent arteriolar wall, resulting in a length shift of and a shift of intensity in the immunoreactive portion of a vessel in an up- or downstream direction of the bloodstream. The changes correspond to the levels of renal renin synthesis and to plasma renin levels under various conditions (6, 31). Both renin mRNA and protein levels were evaluated. The values are presented as means ± SD. For statistics of all experiments, the Mann-Whitney U-test was applied. P < 0.05 was considered significant.
Chemical reagents, kits, and instruments.
-NADPH, NADH, NBT, X-phosphate, levamisole, BSA, and ethidium
bromide were from Sigma (Deisenhofen, Germany). Anti-rabbit peroxidase-antiperoxidase complex and mouse anti-human
-smooth muscle actin antibody were from DAKO (Glostrup, Denmark). Goat anti-rat
COX-2 antibody was from Santa Cruz Biotechnology (Heidelberg, Germany).
Goat anti-rabbit Cy3, donkey anti-goat Cy3, and goat anti-mouse
colloidal gold conjugate were from Dianova (Hamburg, Germany). Silver
enhancement reagent was from Biotrend (Köln, Germany). Rabbit
anti-mouse
1
2-collagen IV antibody was
from Beckton-Dickinson. All chemicals for molecular biology and sheep anti-DIG-alkaline phosphatase conjugate were from Roche (Mannheim, Germany). Slides were viewed in a Leica DMRB microscope equipped with
epifluorescence illumination and interference-contrast optics. Grids
were examined in a Zeiss EM 9 transmission electron microscope.
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RESULTS |
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Clinical parameters. FHH8 and FHH16 rats had moderate but significant hypertension, with mean systolic blood pressure levels of 156 ± 12 (P < 0.05) and 160 ± 17 mmHg (P < 0.05), respectively, compared with 138 ± 18 in the FHL16 group. Proteinuria was elevated only in the older hypertensive group (24 mg/day in FHL16, 19 mg/day in FHH8, and 217 mg/day in FHH16; P < 0.05), indicating advanced nephron damage.
Renal histopathology.
Renal damage was absent from the FHL16 group, occasionally present to a
moderate extent in FHH8, and very prominent in FHH16. Both alterations
of the vasculature and the nephron were encountered. Pathomorphology of
cortical arteries and arterioles in FHH16 included mild-to-significant
hypertrophy of the media, enhanced levels of immunoreactive -smooth
muscle actin, and the presence of intramural PAS-positive deposits
(Fig. 1). Ultrastructural analysis also revealed that vascular remodeling also included degenerative changes of
the smooth muscle cells with loss of myofilaments; degeneration apparently took its origin from the innermost layer of the media. Marked increases in the quantity of interstitial matrix compounds and
thickening of the basement membrane were seen in the arteriolar wall,
preferentially in subendothelial localization. Intima swelling was
obvious, and subendothelial spaces were often widened (Fig. 1).
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Histochemistry of juxtaglomerular vasoactive parameters.
Compared with the normotensive FHL16 group, FHH groups presented
significant augmentation of NOS1 activity and mRNA abundance (Fig.
3) and COX-2 immunoreactive signal in MD
and adjacent TAL cells (Fig. 4). The
preglomerular portion of the afferent arteriole showed marked
enhancements of immunoreactive renin and renin mRNA expression levels,
respectively (Fig. 5). NOS activity, as
expressed by the number of NADPH-d-stained MD cells, was significantly
increased in FHH8 (+153%; P < 0.05) and in FHH16
(+93%; P < 0.05); accordingly, MD cells stained for
NOS1 mRNA transcripts were numerically increased as well in FHH8
(+88%; P < 0.05) and in FHH16 (+98%;
P < 0.05). Thus increased NOS signals in FHH were
evident by significant augmentation of histochemically labeled MD cells
(Fig. 3).
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DISCUSSION |
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The present study revealed a coordinate enhancement of mRNA and activity levels of NOS1 and protein levels of COX-2 in the MD and juxtaglomerular portion of the TAL and of renin mRNA and protein levels in the afferent arteriole in FHH rats. This phenomenon occurs before the manifestation of glomerular disease and continues at least up to the age of 16 wk.
The observed patterns of FSGS largely corresponded to what has been reported earlier on renal pathogenesis in FHH (24, 26) and were thus in agreement with the rapid progression of the damage leading to chronic renal failure in FHH after ~1 yr (13, 27). The older FHH group also showed a modest-to-medium-strength arteriolopathy of the smaller resistance arterioles. In these vessels, a pronounced media hypertrophy coincided with myocyte degeneration of the innermost media layers, and these changes had also affected the preglomerular portion of the afferent arteriole, a functionally prominent site for the regulation of glomerular perfusion (31).
The animals of the FHH groups in our study were moderately hypertensive. Among the possible causes leading to the progression of renal failure in this rat strain, systemic hypertension may play a significant, although not the central, role in FHH, and blood pressure correlated closely with capillary hypertension and hyperfiltration (36). Accordingly, pharmacological treatment that decreases blood pressure reduced or prevented glomerular and renal vascular damage in FHH (35). However, other hypertensive strains such as spontaneously hypertensive rats (SHR) have a much higher blood pressure but are quite resistant to renal damage unless an additional impact such as uninephrectomy is imposed (15). Because variation in blood pressure in FHH correlates with renal damage only at a rate of 42%, additional adverse factors must be effective (8); in fact, insufficient afferent arteriolar tone in conjunction with a relatively high efferent arteriolar resistance seem to be the key factors leading to glomerular hypertension and consequent damage (36).
We found markedly increased NOS1 enzyme activity and mRNA abundance in the MD of FHH. As established for other models, activation of NOS1 may result in a constitutively increased release of NO from this site (3, 5, 6, 43). Under the given condition of an established hyperfiltration and the probably resulting elevation in distal tubular NaCl load in FHH, an enhanced expression of NOS1, however, is an unexpected finding because this condition should rather reduce than enhance NOS1 activity and synthesis (3, 6, 37). A secondary, reactive upregulation of NOS1 in FHH would therefore seem unlikely, whereas a primary, as yet unidentified, stimulation of NOS1 would appear more likely. As a consequence, enhanced levels of NO from MD may diffuse into the JGA (5), where binding to its receptor, soluble guanylyl cyclase (sGC), could induce a relaxation of intra- and extraglomerular mesangial cells and nearby located vascular cells (2). As a result, basal afferent tone could be inadequately reduced, which would agree with an impaired myogenic autoregulation in FHH compared with FHL (40) and abnormal operating levels of TGF despite an intact responsiveness of this mechanism (41). The resulting elevated PGC may in fact be related to impaired local NO abundance, which is known to affect juxtaglomerular vasoconstrictor mediators (31, 43, 40).
Previous studies have identified the podocyte as the cell type centrally involved in the glomerular structural and functional deterioration in FSGS (25, 26); however, an increased physical impact on the glomerular capillaries in FHH may also require the counteracting forces from the mesangial side (12, 25). Altered NO release from the JGA may therefore alter this parameter as well in pathogenetic respect.
Concomitantly enhanced immunoreactivity for COX-2, the rate-limiting enzyme in prostaglandin and thromboxane synthesis, in MD and adjacent TAL cells is likely to reflect an augmented release of one or several of the biologically active metabolites such as PGE2, PGI2, thromboxane B2, or others (for review, see Refs. 7, 31, and 34). Release of these substances would be in line with previous findings in FHH on enhanced excretion of all eicosanoids, including PGE2, coincident with the onset of hyperfiltration (14), whereas subsequent progressive proteinuria in these rats was associated with an increase in thromboxane B2 and a decrease in PGE2 excretion. Although the array of prostanoids produced by the MD has not been characterized, the primary product synthesized by the TAL is PGE2 (4), which in the setting of volume depletion appears to maintain GFR by dilating the afferent arteriole (20). A recent study has suggested a pathogenetic role for COX-2 in progressive renal failure induced by the reduction of renal mass (42); inhibition of COX-2 significantly reduced the damage, which may have implications for the role of prostaglandins in FHH.
The reason COX-2 is upregulated in FHH is as unclear as that for NOS1, because an augmented filtrate should suppress rather than enhance expression of the enzyme, and an increased NaCl load at the MD substantially decreased expression of the enzyme (44). On the other hand, COX-2 may be activated by NO that probably interacts with its heme domain by means of the intermediate coupling product peroxynitrite (28). Accordingly, renal cortical COX-2 is likely to be under the stimulatory control of NO, as has been suggested from studies in rabbit (30), rat (9, 33), and mice with targeted deletion of NOS1 (Bachmann S and Theilig F, unpublished observations). Therefore, enhanced NO levels generated in MD may be related to the enhanced juxtaglomerular COX-2 expression seen in FHH.
We also observed an enhanced expression of renin in the afferent arteriole of FHH. This result agrees with previous findings on coordinate changes in the juxtaglomerular levels of NOS1 and renin (6, 31, 37). In fact, NO may exert a direct, cGMP-mediated effect on the granular renin-producing cells because these were shown to contain significant amounts of soluble guanylyl cyclase (2). In addition, there are several lines of evidence that COX-2 may also be directly involved in the transmission of MD-stimulated renin release (17, 38).
Although data on plasma renin activity in FHH are somewhat controversial (16, 21, 27, 29), it is evident that elevated renin levels and elevated blood pressure correlated with variations in renal damage (27). We also found that FHH were protected from renal damage by an inhibitor of the angiotensin-converting enzyme, especially when it was administered before the development of FSGS (35, 41, 43). Local upregulation of the type 1 angiotensin II receptor may also be involved in the regulation of glomerular perfusion because elevated levels of the receptor were found in FHH (22).
Altered renal gene expression in FHH is likely to be responsible for the susceptibility to FSGS because transplantation of FHH kidney into a normotensive, renal damage-resistant strain has proven that the susceptibility for renal damage depended on the graft kidney when the recipient was exposed to high blood pressure (23). Genetic analysis of this strain has identified two genes that are responsible for a proportion of the genetic variation related to renal damage, and one locus on chromosome 1, Rf-1, was reported to explain 37% of the total variance in proteinuria, but, in addition, a number of other loci were detected as well, thus underscoring the complexity of the genesis of renal defects in FHH (8). A clear relationship to the aberrant juxtaglomerular gene expression observed in this study thus awaits further clarification.
In conclusion, we have observed enhanced expression of epithelial NOS1 and COX-2 at the JGA, along with increased renin expression in the glomerular afferent arteriole. In other models, it has been shown that locally enhanced NOS1 and COX-2 activity may affect local vascular tone. These changes may thus have implications for the experimentally established hyperfiltration in FHH. The enhanced renin expression may be related as well to the pathogenesis in this rat model. An application of selective pharmacological inhibitors will be necessary to clarify these issues. A potential link between the genetic variations in FHH and the alterations of juxtaglomerular gene expression remains to be discovered.
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ACKNOWLEDGEMENTS |
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We thank Stefan Resch for help in the preparatory steps leading to this study and Rosemarie Tapp for providing the electron micrograph (Fig. 1B).
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FOOTNOTES |
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This work was supported by funds from the Deutsche Forschungsgemeinschaft (Ba 700/10-2).
Address for reprint requests and other correspondence: S. Bachmann, Anatomie der Charité, Elektronenmikroskopie, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany (E-mail: sbachm{at}charite.de).
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.
Received 18 August 2000; accepted in final form 5 December 2000.
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