Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy

Abstract

Despite the progress in the therapeutic treatment of diabetes mellitus, diabetic nephropathy is one of the major complications of diabetes and the single largest cause of endstage renal diseases. Histologically, early diabetic nephropathy is characterized by glomerular hypertrophy and the inappropriate dilatation of afferent arterioles, which are believed to be associated with hyperfiltration and are followed by thickening of the glomerular basement membrane and accumulation of mesangial matrix [1,2]. The pathogenesis of glomerular hypertrophy and afferent arteriolar dilatation due to diabetes is, however, still not clear.Nitric oxide (NO) has been identified as a pleiotropic intercellular messenger that regulates a variety of cellular functions [3] and an endothelium-derived relaxing factor that inhibits contraction of vascular smooth muscles, as well as the adhesion or aggregation of platelets [4]. Three isoforms of this enzyme have Diabetologia (1998) Summary The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO 2 / NO 3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO 2 /NO 3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration. [Diabetologia (1998 Keywords Nitric oxide (NO), endothelial cell nitric oxide synthase (ecNOS), diabetic nephropathy, afferent arterioles, glomerular hyperfiltration Received: 5 January 1998 and in revised form: 27 April 1998Corresponding author: H. Sugimoto MD., Department of Med...

Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney

“…However, considering the fact that eNOS and CAV-1 form an inhibitory complex, reduced CAV-1 expression may be interpreted as a factor favoring NOS enzymatic activity. This observation would be consistent with data suggesting enhanced NO dependency of renal hemodynamics in hyperfiltering diabetic rats and the role of NO in the pathogenesis of hyperfiltration (7)(8)(9) and with those reports suggesting a role for eNOS-derived NO in this process (26,32,33). However, the latter reports relied on measurements of eNOS expression and constitutive renal NOS activity, and the role of eNOS could not be verified by measurement of renal hemodynamic responses to specific eNOS inhibitors.…”

“…Importantly, observed changes in eNOS expression, posttranslational modifications, and subcellular targeting, as well as CAV-1 expression, were reversed or attenuated by intensive insulin treatment. Despite abundant evidence of impaired endotheliumdependent vasodilation and reduced NO renal bioavailability in renal and nonrenal vasculature in diabetes (3,4,6,29,30), previous studies have reported normal (31) or enhanced (26,(32)(33)(34) expression of eNOS in the diabetic kidney and, in some reports, even enhanced NO production in diabetic renal cortex (31). In accord with Ishii et al (31), we found no differences between control and diabetic rats with respect to whole-cell eNOS expression.…”

Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects

“…Enhanced endothelial nitric oxide synthase (eNOS) activity has been suggested to mediate renal hyperfiltration [31]. Indeed, chronic NOS inhibition abolishes glomerular hyperfiltration [32], and the afferent arterioles of streptozotocin diabetic rats show high levels of eNOS expression [33]. This could be particularly relevant to our study, as we used the development of microalbuminuria as the study endpoint.…”

Diabetes-induced changes in endothelial mechanisms implicated in rabbit carotid arterial response to 5-hydroxytryptamine

“…the course of the disease Pieper et al, 1998 . An excessive NO production has also been suggested to contribute to the renal hyperfiltration and hyperperfusion that charac-Ž terise early diabetic nephropathy Sugimoto et al, 1998;. Choi et al, 1999 .…”