Chronic renal impairment and DDAH2-1151 A/C polymorphism determine ADMA levels in type 2 diabetic subjects

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased levels of ADMA cause impaired vasodilation, leading to endothelial dysfunction and a higher risk for cardiovascular events. In patients with a chronic kidney disease, increased ADMA levels are reported to play a role in the pathogenesis of accelerated atherosclerosis and are an independent risk marker leading to end-stage renal disease and mortality. Circulating ADMA is metabolized by the action of dimethylarginine dimethylamino hydrolase (DDAH) and DDAH2 isoform is the most prevalent in tissues expressing endothelial NOS. DDAH and NOS are co-expressed in the same kidney regional sites supporting the hypothesis that a strict and specific regulation of intracellular ADMA levels is crucial for NO generation in the kidney. Starting from these findings, the study aims to investigate the role of DDAH2 gene promoter polymorphism at position -1151 A/C in determining the levels of ADMA in type 2 diabetic patients (T2DM) with chronic renal impairment. Three groups of carefully selected subjects of both sexes were enrolled and compared. The first group (control subjects) comprised 286 non-diabetic subjects (mean age 55.8 ± 11.4 years), the second group (T2DM uncomplicated subjects) was made up of 322 T2DM subjects without complications (mean age 64.9 ± 9.6 years) whereas the third group (T2DM CRF subjects) included 110 T2DM patients with chronic renal impairment. The rs805304 DDAH2-1151 A/C promoter polymorphism was determined by a polymerase chain reaction-restriction fragment length polymorphism approach. Results T2DM CRF subjects showed significant increased plasma levels of ADMA with respect to those of T2DM uncomplicated subjects and control subjects (0.51 versus 0.39 versus 0.37 μmol/L, P = 0.002, respectively). Analysis of variance showed an interaction between DDAH2-1151 C carrier and groups on ADMA plasma levels (F = 4.36; P < 0.05). ADMA plasma levels were also dependent on groups (F = 4.96; P < 0.01). Our work demonstrates that rs805304 DDAH2-1151 polymorphism plays a central role in determining ADMA in diabetic renal impairment, where patients with DDAH2-1151 C carriers showed the highest ADMA levels. This unfavourable genetic profile is highlighted by pathological kidney conditions such as diabetic CRF. These findings could open new insights on the pathways involving ADMA/DDAH/NOS in the development and progression of chronic renal impairment and therefore of the other micro- macrovascular diabetic complications.