Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis

Abstract

BackgroundNitric oxide (NO) has numerous functions in the kidney, including control of renal and glomerular hemodynamics, by interfering at multiple pathological and physiologically critical steps of nephron function. Endothelial NOS (eNOS) gene has been considered a potential candidate gene to diabetic nephropathy (DN) susceptibility. Endothelial nitric oxide synthase gene (eNOS-3) polymorphisms have been associated with DN, however some studies do not confirm this association. The analyzed polymorphisms were 4b/4a, T-786C, and G986T.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was used in this report. Case–control studies that had diabetic patients with DN as cases and diabetic patients without nephropathy as controls, as well as that evaluated at least one of the three polymorphisms of interest were considered eligible. All studies published up until December 31st, 2012 were identified by searching electronic databases. Hardy-Weinberg equilibrium assessment was performed. Gene-disease association was measured using odds ratio estimation based on the following genetic contrast/models: (1) allele contrast; (2) additive model; (3) recessive model; (4) dominant model and (4) co-dominant model.ResultsTwenty-two studies were eligible for meta-analysis (4b/a: 15 studies, T-786C: 5 studies, and G984T: 12 studies). Considering 4b/a polymorphism, an association with DN was observed for all genetic models: allele contrast (OR = 1.14, CI: 1.04-1.25); additive (OR = 1.77, CI: 1.37-2.28); recessive (OR = 1.77, CI: 1.38-2,27); dominant (OR = 1.12, CI: 1.01-1.24), with the exception for co-dominance model. As well, T-786C polymorphism showed association with all models, with exception for co-dominance model: allele contrast (OR = 1.22, CI: 1.07-1.39), additive (OR = 1.52, CI: 1.18-1.97), recessive (OR = 1.50, CI: 1.16-1.93), and dominant (OR = 1.11, CI: 1.01-1.23). For the G894T polymorphism, an association with DN was observed in allelic contrast (OR = 1.12, CI: 1.03-1.25) and co-dominance models (OR = 1.13, CI: 1.04-1.37).ConclusionsIn the present study, there was association of DN with eNOS 4b/a and T-786C polymorphism, which held in all genetic models tested, except for co-dominance model. G894T polymorphism was associated with DN only in allele contrast and in co-dominance model. This data suggested that the eNOS gene could play a role in the development of DN.

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat

“…Furthermore, asymmetric dimethyl arginine, an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is associated with the development and progression of diabetic nephropathy in patients (Lajer et al, 2008;Hanai et al, 2009;Shibata et al, 2009). Consistent with these studies, eNOS polymorphisms resulting in reduced enzyme expression or function have been associated with diabetic nephropathy (Dellamea et al, 2014). In an analysis of preclinical models of disease, it was demonstrated that deficiency of eNOS in db/db diabetic mice produced a renal gene expression profile that more closely resembled human diabetic nephropathy, compared with db/db mice with intact eNOS (Hodgin et al, 2013).…”

The Puerarin improves renal function in STZ-induced diabetic rats by attenuating eNOS expression

“…9 Several studies have demonstrated that increased eNOS expression seems to be involved in the development and progression of DN. 10,11 Puerarin (daidzein-8-C-glucoside) is the main isoflavone isolated from the Chinese medicinal herb Ge-gen, the root of the wild leguminous creeper Pueraria lobata (kudzu root). 12 It has been shown effective in the treatment of kidney diseases, such as nephrotoxicity, acute kidney injury and nephropathy.…”

Endothelial Nitric Oxide Synthase (eNOS) Glu298Asp Gene Polymorphism (G894T) as a Risk Factor for Type 2 Diabetes Mellitus in the Tunisian Population

“…NO may play a role in insulin resistance and type 2 diabetes .NO is known to modulate the metabolism of glucose and hepatic and peripheral insulin secretion [13]. Indeed, endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) is involved in the pathogenesis of insulin resistance and hypertension [21].…”

“…Elevations in CRP are associated with an increased risk for insulin resistance which contributes to endothelial dysfunction, predisposing the endothelium to a hyper inflammatory and thrombotic condition [13].…”