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.
Highlights
About 30% of patients with type 2 diabetes mellitus develop clinically overt nephropathy [1]. It appears that in humans 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
DN is histologically defined by thickening of the glomerular basement membrane, increased fractional mesangial volume, and podocyte abnormalities [2]
Summary
About 30% of patients with type 2 diabetes mellitus develop clinically overt nephropathy [1]. G894T was linked to increased risk of macroalbuminuria and progression from microalbuminuria to macroalbuminuria, with declining glomerular filtration rate as serum creatinine value rises progressively, culminating in ESRD [66,67], independent of other risk factors These polymorphisms seem to change eNOS expression and to be associated with different levels of eNOS that make these associations clinically plausible. Abreviations ADMA: Dimethylarginine; AKT: Protein kinase B; CKD: Chronic kidney disease; DN: Diabetic nephropathy; eNOS: Endothelial nitric oxide synthase; GFR: Glomerular filtration rate; iNOS: Inducible nitric oxide synthase; nNOS: Neuronal nitric oxide synthase; NO: Nitric oxide; NOS: Nitric oxide synthase; NOSs: Nitric oxide synthases; NOS-1: Neuronal nitric oxide; NOS-2: Induciblenitric oxide; NOS-3: Endothelialnitric oxide; PI3K: Phosphatidylinositide 3-kinases; UCP2: Uncouplingprotein 2; VEGF: Vascular endothelial growth factor. Author details 1Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 2Endocrine Division of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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