Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University School of Medicine, Sendai, Japan
Correspondence and offprint requests to: Shuji Arima, MD, Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University School of Medicine, 11 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan. Email: shuarima{at}mail.cc.tohoku.ac.jp
Keywords: atrial natriuretic peptide; calcium and potassium channel; insulin; myogenic response; reninangiotensin system; tubuloglomerular feedback
Introduction
In diabetes and various renal diseases, glomerular capillary pressure (PGC) is elevated due to either decreased afferent arteriolar resistance or increased efferent arteriolar resistance, or both [1,2]. Regardless of initial insults, however, glomerular hypertension causes endothelial, mesangial and podocyte injuries, which ultimately result in glomerulosclerosis [3]. This decreases the number of functioning nephrons and further elevates PGC, thereby resulting in a vicious cycle. Thus, such alterations in glomerular haemodynamics critically contribute to the pathophysiology of diabetic nephropathy; particularly, it greatly influences the mode of progression of glomerular damage [2]. It is therefore important to understand mechanisms that alter glomerular haemodynamics in diabetes mellitus. This article reviews the mechanisms underlying altered vascular resistance of afferent or efferent arterioles in diabetic nephropathy.
Calcium and potassium channels
Afferent arteriolar dilation observed in early stage diabetes is associated with its diminished responses to a variety of vasoconstrictor stimuli. Since the vascular tone of afferent arterioles depends on the Ca2+ influx into the vascular smooth muscle cells through voltage-dependent calcium channels (VDC) [4], functional impairment of these channels may contribute to the afferent arteriolar dilation. Indeed, Carmines et al. [5] have demonstrated that afferent arteriolar contractile responses to both BAYK8644 (a VDC agonist) and K+-induced depolarization are attenuated during the hyperfiltration stage of streptozotocin-induced diabetic rats (2 weeks after onset). In addition, they have also found that depolarization-induced Ca2+ influx and the resulting increase in intracellular [Ca2+]i are attenuated in the afferent arterioles of diabetic rats and that these abnormal responses are rapidly restored by normalization of extracellular glucose levels. These observations suggest that hyperglycaemia impairs the function of afferent arteriolar VDC, resulting in the diminished vasoconstrictor responses of afferent arterioles. It is also possible that dysregulation of membrane potential involving a functional overexpression of K+ channels promotes membrane hyperpolarization, thereby reducing Ca2+ influx through VDC and causing vasodilation. Ikenaga et al. [6] have examined the possible contribution of ATP-sensitive K+ (KATP) channels to afferent arteriolar dilation during the early stage of diabetes. They found that KATP channel agonists (pinacidil and PCO-400) cause more potent afferent arteriolar dilation in diabetic rats than normal rats, suggesting that the functional availability of KATP channels or their impact on membrane potential is increased during the early stage of diabetes. Moreover, glibenclamide (a KATP channel antagonist) caused a concentration-dependent constriction in early diabetic but not normal afferent arterioles. From these findings it is implicated that exaggerated function of KATP channels also contributes to the afferent arteriolar dilation during the early stage of diabetes. Such altered regulatory mechanisms of membrane potential and Ca2+ influx may act synergistically to promote the afferent arteriolar dilation during the early stage of diabetes.
Tubuloglomerular feedback
In each nephron of the mammalian kidney, the tubule returns to the hilus of the parent glomerulus, forming the juxtaglomerular apparatus, which displays a unique arrangement of afferent and efferent arterioles, extraglomerular mesangial cells and the macula densa (MD) [7]. Because of this intimate anatomical relationship, the MD senses changes in the composition of the tubular fluid and controls the single nephron glomerular filtration rate (SNGFR) by adjusting the vascular resistance of afferent arterioles [8]; the mechanism is called tubuloglomerular feedback (TGF) [9,10]. The TGF is highly intricate, synchronizing oscillations of the Na+/Cl concentration and the SNGFR [11]. It plays an important role in renal autoregulation and homeostasis of body fluids and electrolytes. It has been demonstrated that fractional reabsorption of fluid and electrolytes in the proximal tubule is increased in the early stages of diabetes in both humans [12] and experimental animals [13,14]. These changes may relate to increased Na+/glucose co-transport [13]. Such increase in fractional tubular reabsorption upstream of the MD could inhibit the TGF signals by lowering the electrolyte concentration at the MD, resulting in an increased SNGFR due to afferent arteriolar dilation. In addition, it has been demonstrated that nitric oxide (NO) derived from neuronal NO synthase (NOS1), which is predominantly expressed in the MD, counteracts TGF-mediated afferent arteriolar vasoconstriction [15,16]. Interestingly, NOS1-mediated NO production in MD is elevated in diabetes, resulting in decreased afferent arteriolar resistance [17]. Thus, NOS1-derived NO is also involved in the pathogenesis of glomerular hypertension in early diabetes.
Myogenic response
The term myogenic response refers to the ability of vascular smooth muscle to constrict in response to increases in transmural pressure, causing dilatation when the pressure is decreased. This response is important in establishing a close link between vascular tone and regulation of regional blood flow as well as capillary pressure [18]. In the kidney, increasing perfusion pressure causes myogenic constriction of preglomerular resistance vessels, especially the afferent arterioles, and acts to prevent an excessive rise in the PGC when the systemic pressure is elevated. Using the isolated perfused hydronephrotic kidney technique, Hayashi et al. [19] have demonstrated an attenuated myogenic response of the afferent arteriole in diabetes. They have also found that inhibition of prostaglandin synthesis normalized the myogenic response of diabetic afferent arterioles, suggesting an involvement of vasodilator prostaglandins in the pathogenesis of impaired myogenic responses in diabetes. In addition, since myogenic response-mediated constriction of afferent arterioles depends on the Ca2+ influx into the vascular smooth muscle cells through VDC, impaired function of this channel (as mentioned above) may also contribute to the attenuated afferent arteriolar myogenic responses.
Insulin
Several studies indicate that insulin plays an important role in vascular smooth muscle contraction. Therefore, insulin deficiency per se needs to be considered as a mechanism contributing to the afferent arteriolar dilation in diabetes. Bank et al. [20] were the first to suggest that insulin deficiency plays an important role in the genesis of reduced renal vascular resistance in diabetes. They demonstrated that insulinopenia impairs Ca2+ movement through VDC in the diabetic rat renal vasculature. Thus, it is possible that vasoconstrictor agents which initiate calcium entry into the renal vascular smooth muscle cells lose their effectiveness in the absence of insulin. Scholey and Meyer [21] reported that infusion of insulin into diabetic rats lowered PGC, whether plasma glucose concentration was clamped at the hyperglycaemic level or was allowed to fall to the normal range. Furthermore, Juncos and Ito [22] have provided direct evidence that insulin decreases PGC through its haemodynamic actions. They have demonstrated that physiological concentrations of insulin cause afferent arteriolar constriction and efferent arteriolar dilation. These observations strongly support the notion that insulin deficiency directly contributes, at least in part, to the glomerular hypertension in diabetes.
Atrial natriuretic peptide
Atrial natriuretic peptide (ANP) is elevated in the plasma of diabetic animals [23] and humans [24] and the levels vary inversely with the degree of metabolic control of glucose [25]. It has been demonstrated that ANP causes dilation in afferent arterioles and constriction in efferent arterioles [26] and that administration of ANP in normal rats raises the PGC and increases GFR [27]. Therefore, it is reasonable to consider excess endogenous ANP as a mediator of glomerular hyperfiltration and hypertension in diabetes. Ortola et al. [23] studied the relationship between GFR and ANP in diabetic rats. They found that the plasma ANP concentration was 280 pg/ml in rats with moderately controlled diabetes (average blood glucose: 326 mg/dl), but 158 pg/ml in rats with tightly controlled diabetes (average blood glucose: 85 mg/dl). In addition, they also found that GFR was elevated in the former, but normal in the latter. When the authors infused an antiserum directed against ANP into the diabetic rats with hyperfiltration, they found a prompt decline in GFR towards normal with no alteration of blood pressure or blood glucose. Zhang et al. [28] also demonstrated that a specific antagonist of the ANP receptor ameliorates glomerular hyperfiltration in diabetic rats. These observations provide strong support for the view that ANP is a mediator of glomerular hyperfiltration/hypertension in diabetic rats. In addition, ANP might contribute to the glomerular hypertension by antagonizing the vasoconstrictor actions, such as angiotensin II (Ang II) and norepinephrine [29], on afferent arterioles.
Reninangiotensin system
Although diabetic nephropathy has traditionally been considered as a low renin state, considerable experimental and clinical evidence suggests that the intrarenal reninangiotensin system (RAS) plays an important role in the pathophysiology of diabetic nephropathy. This may be because plasma renin activity (PRA) does not accurately reflect the activity of RAS in the kidney. Evidence suggests that hyperglycaemia activates the intrarenal RAS, leading to a stimulation of the local production of Ang II, which increases renal vascular resistance (RVR), reduces renal blood flow and may exert feedback inhibition of systemic renin release [30]. Anderson et al. [31] performed micropuncture studies in diabetic rats and showed that glomerular hypertension was significantly reduced with an angiotensin-converting enzyme (ACE) inhibitor, but not with a calcium channel blocker, even though there was a comparable lowering of systemic blood pressure with both therapies. They also found that SNGFR and glomerular plasma flow rate (QA) remained similar in both treated groups. Thus, the reduction in PGC in the ACE inhibitor-treated rats was largely due to a greater decrease in efferent than in afferent arteriolar resistance, consistent with a suppression of Ang II action. Miller [32] reported an increased RVR and filtration fraction (FF) with maintenance of GFR in early type 1 diabetic patients with moderate hyperglycaemia, implying a predominant effect of hyperglycaemia to increase the vascular resistance of efferent arterioles. In addition, such renal haemodynamic responses were completely reversed by administration of losartan (an AT1 receptor antagonist) and the stimulatory effects of Ang II infusion on RVR and FF were blunted during hyperglycaemia, indicating the activation of intrarenal RAS in early type 1 diabetic patients. The situation in type 2 diabetes appears to be similar. In patients with type 2 diabetes and nephropathy, Price et al. [33] showed a significant suppression of PRA compared with healthy subjects, but an enhanced renal vasodilatory response to irbesartan (an AT1 receptor antagonist). In patients with diabetes, PRA increased progressively in response to irbesartan. These data are consistent with the hypothesis that there is an activation of the intrarenal RAS in diabetic nephropathy with feedback inhibition of juxtaglomerular cell renin release by elevation of local Ang II levels (and perhaps volume expansion secondary to enhanced tubular sodium reabsorption).
In summary, measurements of circulating components of the RAS in experimental or human diabetes do not accurately predict the state of the RAS activation or its response to blockade at the kidney level. This observation, coupled with the knowledge that therapy with ACE inhibitors or AT1 receptor antagonists exerts beneficial effects on proteinuria and disease progression, suggests that there may be a local activation of RAS within the kidney. Such locally produced Ang II is expected to contribute to the development of glomerular hypertension, because Ang II preferentially constricts efferent arterioles compared to afferent arterioles.
Other factors and concluding remarks
In addition to factors mentioned above, other vasoactive substances (such as endothelium-derived NO and vasodilator prostaglandins) or multiple metabolic alterations associated with diabetes (such as hyperglycaemia, increased oxidative stress, presence of ketone bodies and the intracellular accumulation of sorbitol) have been implicated in the pathogenesis of glomerular hypertension [34]. Thus, the pathogenesis of glomerular haemodynamic abnormalities that cause glomerular hypertension in diabetes is undoubtedly multifactorial. Although glomerular hypertension (or glomerular hyperfiltration) helps to compensate for increased renal tubular reabsorption in diabetes, these changes increase glomerular capillary wall stress and cause glomerular cell proliferation, matrix accumulation and eventually glomerulosclerosis. Thus, improvement of these abnormalities is clearly required for the management of patients with diabetic nephropathy. In addition, since transmission of systemic blood pressure to the glomeruli is facilitated, strict control of systemic blood pressure would be critical in order to prevent the progression of renal dysfunction. Furthermore, measures to improve renal autoregulation by a low protein diet [35] will be of considerable importance.
Acknowledgments
The authors thank Miss Hiroko Kato and Miss Mari Goko for their secretarial assistance in preparing the manuscript.
Conflict of interest statement. None declared.
References