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      Nitric oxide system and diabetic nephropathy

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          Abstract

          About 30% of patients with type 2 diabetes mellitus develop clinically overt nephropathy. Hyperglycemia is necessary, but not sufficient, to cause the renal damage that leads to kidney failure. Diabetic nephropathy (DN) is a multifactorial disorder that results from interaction between environmental and genetic factors. In the present article we will review the role of the nitric oxide synthase (NOS) in the pathogenesis of DN.

          Nitric oxide (NO) is a short-lived gaseous lipophilic molecule produced in almost all tissues, and it has three distinct genes that encode three NOS isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS).

          The correct function of the endothelium depends on NO, participating in hemostasis control, vascular tone regulation, proliferation of vascular smooth muscle cells and blood pressure homeostasis, among other features. In the kidney, NO plays many different roles, including control of renal and glomerular hemodynamics. The net effect of NO in the kidney is to promote natriuresis and diuresis, along with renal adaptation to dietary salt intake.

          The eNOS gene has been considered a potential candidate gene for DN susceptibility. Three polymorphisms have been extensively researched: G894T missense mutation (rs1799983), a 27-bp repeat in intron 4, and the T786C single nucleotide polymorphism (SNP) in the promoter (rs2070744). However, the potential link between eNOS gene variants and the induction and progression of DN yielded contradictory results in the literature.

          In conclusion, NOS seems to be involve in the development and progression of DN. Despite the discrepant results of many studies, the eNOS gene is also a good candidate gene for DN.

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          Most cited references 64

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          Nitric oxide: a physiologic messenger molecule.

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            Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy.

            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.
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              eNOS, metabolic syndrome and cardiovascular disease.

               Paul Huang (2009)
              Large epidemiologic studies have established that diabetes, hyperlipidemia and obesity all increase the risk for cardiovascular disease. However, the precise mechanisms by which these metabolic disorders increase the propensity to develop atherosclerosis are not known. Recently, the concept of the metabolic syndrome - a constellation of conditions including obesity, hypertension, hyperlipidemia and insulin resistance - has received much attention. Studies on the metabolic syndrome might enable a better understanding of the underlying biological mechanisms that lead to cardiovascular disease. This review focuses on endothelial nitric oxide synthase and summarizes evidence that a reduction in the bioavailability of endothelium-derived nitric oxide serves as a key link between metabolic disorders and cardiovascular risk.
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                Author and article information

                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central
                1758-5996
                2014
                12 February 2014
                : 6
                : 17
                Affiliations
                [1 ]Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
                [2 ]Endocrine Division of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
                Article
                1758-5996-6-17
                10.1186/1758-5996-6-17
                3928920
                24520999
                Copyright © 2014 Dellamea et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

                Categories
                Review

                Nutrition & Dietetics

                enos, g894t, diabetic nephropathy, diabetes, 4b/a, t786c, nos-3, polymorphism

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