eNOS Glu298Asp Polymorphism and Endothelial Dysfunction in Patients with and without End-stage Renal Disease

Autor: Dilara Kaman, Kadir Ateş, Nevin Ilhan, Necip Ilhan, Hüseyin Çeliker
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Balkan Medical Journal, Vol 33, Iss 2, Pp 128-137 (2016)
ISSN: 2146-3131
2146-3123
Popis: Endothelial dysfunction and impaired regulation of nitric oxide (NO) system has emerged as the characteristics of chronic kidney diseases (CKD). The accumulation of asymmetric dimethylarginine (ADMA) plays a role in the impairment regulation of NO in these patients; however, the mechanism of these disorders is not clear. Increased levels of ADMA and NO bioavailability reduction play a vital role in the pathogenesis of many diseases like coronary atherosclerosis, CKD or diabetes mellitus (1). Morever, accumulation of reactive oxygen species by the increasing NO leads to atherogenesis, hence a over production may also damage cells and tissues (2). Oxidative stress has a very considerable role in the endothelial dysfunction, vascular damage and in the development of cardiovascular diseases. Some of these mechanisms are associated with the oxidative inactivation of NO production and the inhibition of NO synthase activity by free oxygen radicals (3). Earlier studies have shown oxidant/antioxidant imbalance-elevated oxidative damage, reduced antioxidant levels and impaired NO bioactivity- in patients of hemodialysis, resulting in high malondialdehyde levels demonstrated as an indicator of lipid peroxidation (4,5). Nitric oxide, has a crucial role in the vascular homeostasis, regulation of blood flow and blood pressure, is synthesized in the endothelium by a constutive endothelial nitric oxide synthase (eNOS) enzyme. NO production may be effected by several allelic variants of the eNOS gene. eNOS gene polymorphism occurs when a guanine turns into thymidine substitution at position 894 within the exon 7, leads to a change from glutamic acid to aspartic acid at codon 298 (Glu298Asp) in the eNOS protein, is associated with decreased enzyme activity of eNOS and basal NO production, and has been determined to be clinically important for several diseases (6,7). Some reasons like decreased NO synthesis, eNOS gene polymorphisms, and/or arginine defiency may cause increased circulating NOS inhibitors levels, which contributes to an increase in arterial pressure or intraglomerular hypertension in CKD patients (8). NO synthesis is inhibited by the dimethylarginines (DMAs), which are accumulated in plasma during CKD (9). Many studies have shown that the increased level of asymmetric dimethylarginine (ADMA), leads to development of endothelial dysfunction via decreased NO formation in various diseases. Therefore, it is expressed that increased ADMA levels are estimate of future cardiovascular events and overall mortality rate in CKD (10–12). The stereo-isomer of ADMA (SDMA) is eliminated almost substantially by urinary excretion; whereas main elemination pathway of ADMA is enzymatic degradation by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. DDAH activity is play a role in regulation of plasma ADMA levels, provides of ADMA removal, and contributes to the pathogenesis of endothelial dysfunction in CKD (13). Today, as a uremia toxin, ADMA is gathered in End-stage Renal Disease (ESRD) patients and increased plasma ADMA concentration is interacted with oxidative stress. Plasma ADMA accumulation has been identified as a predictive factor for Cardiovascular Diseases (CVDs) and causes of mortality associated with ESRD. However, it is still unknown whether the eNOS gene polymorphisms would mediate the cardiovascular prognosis of ESRD patients. Various polymorphisms of eNOS gene were identified. The eNOS gene, a common variant modifies its coding sequence for Glu298Asp (rs1799983). This variant has been found to be connected with hypertension, diabetic nephropathy, ESRD and nondiabetic ESRD (14–16). Accordingly, the increase of plasma ADMA levels during CKD has suspected to be a factor in the progression of CKD (17–20). We examined the relationship between the eNOS Glu-298Asp gene polymorphism by different dialysis treatments and whether it depends of DMA levels to determine vascular damage in ESRD patients. Although there are reports of various countries, there is lack of data from Turkey in the literature. Therefore, this is the first comprehensive ESRD study evaluating a combination of both genetic and biochemical parameters carried out in Turkey.
Databáze: OpenAIRE
Externí odkaz: