Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is a multifunctional mediator that has been implicated in the short-term hemodynamic alterations that occur in acute streptozocin (STZ)-induced diabetes. We investigated the role of NO produced by inducible nitric oxide synthase (iNOS) in chronic STZ diabetic nephropathy. Diabetes was induced in C57BL/6 and iNOS knockout (KO) mice with two intraperitoneal injections of STZ, 100 mg/kg. Animals were maintained without insulin treatment for 40 weeks. There were no significant differences between the strains in blood urea nitrogen (BUN), serum creatinine or glucose concentration, or urinary protein excretion during the entire observation period. Urinary nitrite + nitrate excretion was significantly lower in iNOS KO mice compared to control animals at all time points; in C57 mice, urinary nitrite declined progressively with more prolonged duration of diabetes. Renal hypertrophy (kidney weight/body weight) was noted in both strains of mice. However, histopathological assessment of renal tissue specimens at 16 and 40 weeks demonstrated increased mesangial hypercellularity and expansion as well as more prominent tubulointerstitial fibrosis in iNOS KO versus C57 mice. These changes were accompanied by increased interstitial deposition of type I collagen at 16 and 40 weeks in iNOS KO mice. Glomerular basement membrane staining for type IV collagen was also increased at 40 weeks in diabetic iNOS KO mice. While iNOS protein was undetectable in any of the kidney specimens obtained from either strain, eNOS was present throughout the course of chronic STZ diabetes. Moreover, eNOS expression was significantly increased by approximately 40% at 16 and 40 weeks of observation in iNOS KO versus C57 mice. There was no difference in renal cortical malondialdehyde content between the strains early or late in the disease course. In time control animals, there was no evidence of renal histopathological damage in iNOS KO or C57 mice after 40 weeks. We conclude that iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic STZ nephropathy. This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.
 ...
PMID:Chronic diabetic nephropathy: role of inducible nitric oxide synthase. 1179 30

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 Ca(2+)-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.
 ...
PMID:Paradoxes of nitric oxide in the diabetic kidney. 1273 64

Nitric oxide (NO) is reported to be involved in the pathogenesis of renal hyperfiltration in the early stage of diabetic nephropathy. We set out to determine whether IGF-I and/or VEGF165 directly stimulate NO production in rat glomeruli and whether the expression of NO synthase (NOS) isoforms as well as eNOS phosphorylation contribute to NO generation by IGF-I and VEGF. Long-term exposure to IGF-I and/or VEGF165 augments NO production through increased eNOS mRNA, protein expression and phosphatidylinositol 3-kinase (PI3-K) signaling pathway plays a major role in this process; short-term exposure to IGF-I and/or VEGF(165) activates eNOS activity via phosphorylation by a PI3-K/Akt dependent pathway. Our data suggest the great possibility that increased endogenous IGF-I and VEGF may be responsible for the up-regulation of eNOS expression and NO production which contributes to glomerular hyperfiltration in early diabetic kidneys. IGF-I is a newly described growth factor that up-regulates eNOS expression and PI3-K plays a major role in this process.
 ...
PMID:Stimulatory effect of IGF-I and VEGF on eNOS message, protein expression, eNOS phosphorylation and nitric oxide production in rat glomeruli, and the involvement of PI3-K signaling pathway. 1505 May 32

Diabetic nephropathy is the leading cause of end-stage renal disease in the Western hemisphere. Endothelial dysfunction is the central pathophysiologic denominator for all cardiovascular complications of diabetes including nephropathy. Abnormalities of nitric oxide (NO) production modulate renal structure and function in diabetes but, despite the vast literature, major gaps exist in our understanding in this field because the published studies mostly are confusing and contradictory. In this review, we attempt to review the existing literature, discuss the controversies, and reach some general conclusions as to the role of NO production in the diabetic kidney. The complex metabolic milieu in diabetes triggers several pathophysiologic mechanisms that simultaneously stimulate and suppress NO production. The net effect on renal NO production depends on the mechanisms that prevail in a given stage of the disease. Based on the current evidence, it is reasonable to conclude that early nephropathy in diabetes is associated with increased intrarenal NO production mediated primarily by constitutively released NO (endothelial nitric oxide synthase [eNOS] and neuronal nitric oxide synthase [nNOS]). The enhanced NO production may contribute to hyperfiltration and microalbuminuria that characterizes early diabetic nephropathy. On the other hand, a majority of the studies indicate that advanced nephropathy leading to severe proteinuria, declining renal function, and hypertension is associated with a state of progressive NO deficiency. Several factors including hyperglycemia, advanced glycosylation end products, increased oxidant stress, as well as activation of protein kinase C and transforming growth factor (TGF)-beta contribute to decreased NO production and/or availability. These effects are mediated through multiple mechanisms such as glucose quenching, and inhibition and/or posttranslational modification of NOS activity of both endothelial and inducible isoforms. Finally, genetic polymorphisms of the NOS enzyme also may play a role in the NO abnormalities that contribute to the development and progression of diabetic nephropathy.
 ...
PMID:Role of nitric oxide in diabetic nephropathy. 1525 73

The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.
 ...
PMID:Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. 1725 94

A growing body of evidence implicates inflammation in the development of diabetic nephropathy. We recently reported that diabetic endothelial nitric oxide synthase knockout (eNOS KO) mice develop advanced glomerular lesions resembling human diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a major factor in diabetic nephropathy, and is known to be chemotactic for macrophages. Herein, we examined the association of VEGF with macrophage infiltration in experimental diabetic nephropathy. Glomerular macrophage infiltration was markedly increased in diabetic eNOS KO mice compared to diabetic C57BL/6 mice, and correlated with glomerular injury, such as mesangiolysis, glomerular microaneurysm and nodular lesions of glomerular sclerosis. An elevation of podocyte VEGF expression correlated with infiltration of Flt-1-positive macrophage in injured glomeruli in diabetic eNOS KO mice, suggesting that VEGF could contribute to macrophage migration. Neither renal nNOS nor iNOS expression was altered in both C57BL/6 and eNOS KO mice. To determine if lack of NO could affect VEGF activation of macrophages, we examined if exogenous NO can block macrophage migration induced by VEGF in in vitro studies. Exogenous NO blocked macrophage migration and hypertrophy in response to VEGF. NO mediated these effects in part by downregulating Flt-1 expression on the macrophage. In summary, NO negatively regulates VEGF-induced macrophage migration by inhibiting Flt-1 expression. The VEGF-endothelial NO uncoupling pathway might partially explain how VEGF causes glomerular disease in diabetes.
 ...
PMID:The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy. 1860 48

Progression of diabetic nephropathy (DN) is manifested by gradual scarring of both the renal glomerulus and tubulointerstitial region. Over the past several years, the general understanding of the pathogenic factors that lead to renal fibrosis in DN has expanded considerably. In this review, some of the important factors that appear to be involved in driving this fibrosing process are discussed, with special emphasis on newer findings and insights. It is now clear that multiple cell types in the kidney contribute to progressive fibrosis in DN. New concepts about bradykinin, TGF-beta and eNOS signaling as well as JAK/STAT activation and the central role of inflammation in both glomerular and tubulointerstitial fibrosis are discussed.
 ...
PMID:New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. 1872 61

VEGF plays protective roles on a variety of non-diabetic renal diseases. However, in diabetes VEGF exhibits deleterious roles to mediate the development/progression of diabetic nephropathy in spite of high VEGF. The protective role of VEGF could be predominantly dependent on its ability to stimulate nitric oxide production in endothelial cell in non-diabetic renal disease. However, it has been known that nitric oxide bioavailability is reduced in diabetes, indicating that diabetic status does not allow high VEGF to lead to an increase in NO bioavailability. As a result, VEGF could engage to NO-independent pathway, and cause deleterious effects on vascular system. Thus, we have hypothesized that uncoupling of VEGF with endothelial NO can be a mechanism by which VEGF causes diabetic nephropathy. We found that diabetic eNOS knockout (KO) mice exhibit masangiolysis, glomerular capillary microaneurysm, Kimmelstiel-Wilson-like nodular lesions, abnormal angiogenesis and a marked macrophage infiltration in addition to mesangial expansion and thickening of GBM, all of that resemble human diabetic nephropathy. Interestingly these lesions were associated with an increase in renal VEGF expression, suggesting uncoupling of VEGF with endothelial NO could be a mechanism. Compatibly, our in vitro experiments demonstrated that VEGF-induced endothelial cell proliferation was enhanced by NO blocking (with LNAME) and suppressed by exogenous NO administration whereas macrophage migration in response to VEGF was inhibited by exogenous NO, suggesting that uncoupling condition could cause abnormal angiogenesis and macrophage infiltration.
 ...
PMID:Uncoupling of VEGF with NO as a mechanism for diabetic nephropathy. 1892 84

While blockade of the renin angiotensin system (RAS) is beneficial in treating many patients with diabetic nephropathy, some patients show a poor response. We hypothesized that the poor response of RAS blockade is attributed to inability to stimulate endothelial nitric oxide. Recently, we reported that diabetic eNOS knockout (KO) mice develop advanced diabetic nephropathy similar to human disease. Here, we tested the hypothesis that blockade of the RAS would be less beneficial in this model than in diabetic wild-type mice. Both enalapril and telmisartan were less effective at reducing renal injury in diabetic eNOSKO mice compared with diabetic wild-type mice. Blood pressure was only transiently reduced by these treatments in diabetic eNOSKO mice and later returned to levels similar to that of untreated diabetic eNOSKO mice. Serum aldosterone tended to be paradoxically higher with enalapril or telmisartan in diabetic eNOSKO mice, whereas these treatments tended to lower aldosterone in diabetic wild-type mice. The pathogenic role of aldosterone was demonstrated by the evidence that spironolactone significantly reduced blood pressure and prevented renal injury. In addition, a higher dose of enalapril also failed to prevent hypertension and renal injury in diabetic eNOSKO mice. In conclusion, an impaired endothelial NO response could lessen the benefit of RAS inhibition in diabetic renal disease. Aldosterone blockade may provide superior protection in this setting.
 ...
PMID:eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin-angiotensin blockade than from aldosterone receptor antagonists. 2004 65

A number of association studies have investigated the role of the nitric oxide synthase 3 (NOS3) gene in the development of diabetic nephropathy (DN). However, results have been inconclusive, largely because the studies have focused on a variety of different polymorphisms and generate inconsistent results. We performed a meta-analysis of 28 association studies focusing on three polymorphisms in the NOS3 gene (G894T (Glu289Asp), 4b/a, and T-786C) and the risk of DN published before July 2009, covering a total of 10,364 subjects. Although significant heterogeneity was initially found in the analysis of G894T, it did not remain when analysis was done by ethnic subgroups. 894T was negatively associated with DN in Caucasian populations of European origin (OR = 0.896, 0.817-0.983, 95% CI), but was positively associated with DN in East Asian (OR = 2.02, 1.20-3.42, 95% CI) and other populations. Association of the 4b/a variant was observed when studies involving microalbuminuria were excluded (OR = 1.19, 1.02-1.39, 95% CI). The T-786C variant showed an overall weak association (OR = 1.16, 1.01-1.34, 95% CI) with little heterogeneity. In summary, our meta-analysis of the effect of NOS3 gene polymorphisms on the risk of DN supports the involvement of the NOS3 gene in the pathogenesis of DN.
 ...
PMID:A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy. 2004 77


1 2 3 4 5 6 Next >>