Asymmetric Dimethylarginine, Endothelial Dysfunction and Renal Disease

Abstract

l-Arginine (Arg) is oxidized to l-citrulline and nitric oxide (NO) by the action of endothelial nitric oxide synthase (NOS). In contrast, protein-incorporated Arg residues can be methylated with subsequent proteolysis giving rise to methylarginine compounds, such as asymmetric dimethylarginine (ADMA) that competes with Arg for binding to NOS. Most ADMA is degraded by dimethylarginine dimethyaminohydrolase (DDAH), distributed widely throughout the body and regulates ADMA levels and, therefore, NO synthesis. In recent years, several studies have suggested that increased ADMA levels are a marker of atherosclerotic change, and can be used to assess cardiovascular risk, consistent with ADMA being predominantly absorbed by endothelial cells. NO is an important messenger molecule involved in numerous biological processes, and its activity is essential to understand both pathogenic and therapeutic mechanisms in kidney disease and renal transplantation. NO production is reduced in renal patients because of their elevated ADMA levels with associated reduced DDAH activity. These factors contribute to endothelial dysfunction, oxidative stress and the progression of renal damage, but there are treatments that may effectively reduce ADMA levels in patients with kidney disease. Available data on ADMA levels in controls and renal patients, both in adults and children, also are summarized in this review.

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

“…The concentrations of ADMA and possibly SDMA were enhanced in renal insufficiency (23). Plasma ADMA concentration increases with declining renal function, with reduced NO production and reduced expression of eNOS, and in case of inflammation and oxidative stress.…”

“…The pathophysiology of raised ADMA concentrations in ESRD could be multifactorial. ADMA, endogenous nitric oxide synthase inhibitor, has been associated with increased oxidative stress in endothelial cells and leads to endothelial dysfunction (23,43,44). The endothelium dysfunction in ESRD patients has been shown by several clinical studies, however the main reason of this defect is not completely explained (45,46).…”

“…Many factors including genetic factors have been well demonstrated for risk of vascular complications in patients with ESRD, even if the certain mechanism of genetic contributions was not fully established yet (19,(23)(24)(25). The information obtained from last researches put forward that NO mediates the function of endothelium-dependent vasodilation which is considerable in vascular function disorders (23 ESRD patients as an indicator of endothelial dysfunction (26).…”

“…Many factors including genetic factors have been well demonstrated for risk of vascular complications in patients with ESRD, even if the certain mechanism of genetic contributions was not fully established yet (19,(23)(24)(25). The information obtained from last researches put forward that NO mediates the function of endothelium-dependent vasodilation which is considerable in vascular function disorders (23 ESRD patients as an indicator of endothelial dysfunction (26). Evidences of this polymorphism for relationship between impaired endothelial function and a decrease in enzymatic activity and production of nitric oxide and vascular-renal disease were reported in several studies (27)(28)(29)(30)(31).…”

The Importance of Peripheral and Local Blood Analysis for Evaluation of Nitric Oxide and Asymmetric Dimethylarginine Before and After Varicocelectomy

“…Also, ADMA can uncouple NOS resulting in the formation of superoxide radicals and low-density lipoproteins and oxidized low-density lipoproteins can induce more ADMA formation in oxidative stress [7]. In that case, we expect ADMA level to decrease in the internal spermatic vein after varicocelectomy surgery.…”