New pathways to renal damage: role of ADMA in retarding renal disease progression.
ABSTRACT In recent years, increasing evidence has been found that chronic kidney disease (CKD) is a strong cardiovascular risk factor, and therefore, the concept of cardiorenal association is well recognized. One possible factor that could explain this link seems to be endothelial dysfunction. It is widely recognized that endothelial dysfunction plays important roles in both the initiation and progression of atherosclerosis. In addition, we have come to understand that endothelial dysfunction may be a causative factor for proteinuria and/or progression of CKD. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous nitric oxide synthase inhibitor in vivo. Plasma levels of ADMA are elevated in patients with CKD and have been found to be a strong biomarker or predictor for future cardiovascular disease (CVD) as well as the progression of renal injury. These findings suggest that elevation of ADMA-mediated endothelial dysfunction may be a missing link between CVD and CKD. In this review, we discuss the biology of ADMA, especially focusing on its role in the progression of CKD.
- SourceAvailable from: Yosuke Nakayama[Show abstract] [Hide abstract]
ABSTRACT: Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury-induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.Kidney International advance online publication, 9 October 2013; doi:10.1038/ki.2013.398.Kidney International 10/2013; · 8.52 Impact Factor
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ABSTRACT: BACKGROUND: Pulmonary hypertension (PH) is an increasingly recognized life threatening complication in Sickle cell disease (SCD), with associated high mortality in adults. The prevalence of PH in children with SCD is still unknown. The etiology and pathophysiologic mechanisms are still not well understood. AIM OF THE STUDY: To assess the plasma levels of asymmetric dimethyl arginine (ADMA) in children with SCD and its correlation with elevated tricuspid regurgitant jet velocity and other hemolytic markers. SUBJECTS & METHODS: This study was carried out on a cohort of patients (30) with SCD and 30 healthy children as a control group. Certain investigations were done for all subjects; CBC, LDH, ferritin, reticulocytic count, bilirubin, AST, ALT, and plasma levels of ADMA. Doppler echocardiography was done for all subjects. RESULTS: The prevalence of high TRV was 30% in SCD patients. ADMA mean plasma level was significantly higher in patients than in controls (0.79 ± 0.15μmol/l and 0.46 ± 0.11μmol/l respectively, p< 0.001). ADMA was significantly higher in patients with high TRV than those with normal TRV (1.10±0.11μmol/l, 0.80±0.06 μmol/l respectively, p<0.001). There was a significant positive correlation between ADMA plasma levels and TRV ≥ 2.5m/s (r=0.475). CONCLUSION: High plasma ADMA levels may be implicated in the pathogenesis of increased tricuspid regurgitant jet velocity in children with SCD. © 2013 John Wiley & Sons A/S.European Journal Of Haematology 04/2013; · 2.55 Impact Factor
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ABSTRACT: The renal resistive index (RRI) measured by Doppler sonography is a marker of microvascular status that can be generalized to the whole of the arterial tree. Its association with large-vessel dysfunction, such as arterial stiffness or the atherosclerotic burden, can help to establish physiopathological associations between macrocirculation and microcirculation. The authors conducted a cross-sectional study of hypertensive patients (n=202) and a healthy control group (n=16). Stiffness parameters, atherosclerotic burden, and determination of the RRI in both kidneys were performed. The average RRI was 0.69±0.08 and was significantly greater in patients with diabetes and chronic kidney disease. Renal resistive index positively correlated with age, creatinine, and albuminuria. Positive correlations were found with arterial stiffness parameters (pulse wave velocity, ambulatory arterial stiffness index, and 24-hour pulse pressure), as well as atherosclerotic burden and endothelial dysfunction measured as asymmetric dimethylarginine in serum. In the multivariate analysis, independent factors for increased RRI were age, renal function, 24-hour diastolic blood pressure, and arterial stiffness. The authors concluded that there is an independent association between renal hemodynamics and arterial stiffness. This, together with the atherosclerotic burden and endothelial dysfunction, suggests that there is a physiopathologic relationship between macrovascular and microvascular impairment.Journal of Clinical Hypertension 02/2014; · 2.36 Impact Factor