Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice

Zhao, Hui; Wang, Suwan; Cheng, Hao; Zhang, Mingzhi; Takahashi, Takamune; Fogo, Agnes B.; Breyer, Matthew D.; Harris, Raymond C.

doi:10.1681/asn.2006070798

Cited by 327 publications

(354 citation statements)

References 44 publications

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“…30,31 In diabetic lepr db/db mice, deficiency of eNOS resulted in accelerated nephropathy with mesangiolysis and early nodular lesions at 26 weeks. 32 However, in the later fasttrack report, limited to renal studies, the authors neither described endothelial injury, significant tubulointerstitial damage nor provided substantial quantitative analysis.…”

Section: Discussionmentioning

confidence: 99%

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Mohan

Reddick

Musi

et al. 2008

Laboratory Investigation

109

119

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Functional consequences of impaired endothelial nitric oxide synthase (eNOS) activity causing organ-specific abnormalities on a diabetic setting are not completely understood. In this study, we extensively characterized a diabetic mouse model (lepr db/db ) in which eNOS expression is genetically disrupted (eNOS À/À ). The eNOS À/À / lepr db/db double-knockout (DKO) mice developed obesity, hyperglycemia, hyperinsulinemia and hypertension. Analysis of tissues from DKO mice showed large islets in the pancreas and fat droplets in hepatocytes. Interestingly, the aorta was normal and atherogenic lesions were not observed. Abnormalities in the aorta including poor re-endothelialization and increased medial wall thickness were evident only in response to deliberate injury. In contrast, significant glomerular capillary damage in the kidney was identified, with DKO mice demonstrating a robust diabetic nephropathy similar to human disease. The vascular and renal impairments in DKO mice were pronounced despite lower fasting plasma glucose levels compared to lepr db/db mice, indicating that eNOS is a critical determinant of hyperglycemia-induced organ-specific complications and their severity in diabetes. Results provide the first evidence that absence of eNOS in diabetes has a greater deleterious effect on the renal microvasculature than on the larger aortic vessel. The DKO model may suggest novel therapeutic strategies to prevent both vascular and renal complications of diabetes. KEYWORDS: diabetes; endothelial dysfunction; eNOS; micro-and macrovasculature; nephropathy and vasculopathy Macro-and microangiopathy including accelerated atherosclerosis and nephropathy are the most common complications of diabetes. Reduced bioavailabilty of nitric oxide (NO), due to impaired nitric oxide synthase (NOS) activity, is implicated in the generation of these abnormalities. 1-3 NO is formed from L-Arginine by three isoforms of NOS with stoichiometric production of L-citrulline. Among the three isoforms, endothelial NOS (eNOS) is constitutively expressed predominantly in the macrovascular endothelium and along the renal microvascular tree. Basal release of eNOS-driven NO by endothelial cells contributes to the maintenance of normal vasodilatory tone and thromboresistance. Under conditions of hyperglycemia and associated increase in advanced glycation end products, there is excessive generation of superoxide, which interacts with NO resulting in the formation of peroxynitrites. The peroxynitrites oxidize tetrahydrobiopterin, an important cofactor involved in normal eNOS activity. The deficiency of tetrahydrobiopterin causes eNOS uncoupling, which results in increased generation of superoxide rather than NO. Overall, superoxide generation is amplified in macrovessels in diabetes with concomitant reduction in the level of bioavailable NO.Nitric oxide also acts as a potent modulator of renal function and controls both afferent and efferent vascular tone, glomerular ultrafiltration coefficient 4,5 and medullary blood flow. 6 However, the pr...

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Section: Discussionmentioning

confidence: 99%

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Mohan

Reddick

Musi

et al. 2008

Laboratory Investigation

109

119

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“…This phenomenon may facilitate the progression of nephropathy in a manner similar to the manner seen in eNOS 2/2 mice: diabetic nephropathy is exacerbated in conjunction with a moderate increase in systolic BP, leading to a more progressive renal phenotype, including tubulointerstitial fibrosis. [50][51][52][53] Podocyte-expressing Nox5 mice exhibit early increases in systolic BP accompanied by progressive tubulointerstitial fibrosis. Although the exact mechanism that elevates BP remains unclear, it is possible that increased superoxide production resulting from aberrant Nox5 activity may lead to decreased NO bioavailability, with consequent decreased vasodilation and increased vascular resistance and elevation of systolic BP.…”

Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

117

122

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NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5 pod+ ). Nox5 pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5 pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension. Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier. 1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction. Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important. [3][4][5][6] Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the

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“…The field of vascular research in DN received a substantial boost in 2006 and 2007 when two groups reported in JASN that diabetic mice null for endothelial nitric oxide synthase (eNOS2/2) recapitulated major structural and functional features of advanced human DN. 2,3 The enzyme eNOS is highly specifically expressed in the endothelium and is responsible for producing the vasodilator nitric oxide, which is thought to contribute to vascular homeostasis. Loss of eNOS-derived nitric oxide activity has been observed in diabetic patients well before the onset of severe end-organ complications (reviewed by De Vriese et al 4 ).…”

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confidence: 99%

The Vasculature in Diabetic Nephropathy

Maski

Parikh

2014

Journal of the American Society of Nephrology

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Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice

Cited by 327 publications

References 44 publications

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

The Vasculature in Diabetic Nephropathy

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