Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

“…Furthermore, endothelial dysfunction was recently reported to be associated with the decline of renal function in hypertensive patients (5). ADMA was reported to be one of the main determinants of endothelial dysfunction in patients with CKD (25), and elevated plasma ADMA levels have been observed in patients with ESRD and mild to moderate CKD (17,26). Short-term elimination of circulating ADMA by hemodialysis was associated with improved endothelial function in ESRD patients (27).…”

Recent advances of animal model of focal segmental glomerulosclerosis

“…129/Sv and Swiss-Webster mice are among the few mouse strains susceptible to developing sclerosis [11]. A 4/6 renal mass reduction results in a milder variant of FSGS, without the induction of hypertension [12].…”

Dimethylarginine Dimethylaminohydrolase Prevents Progression of Renal Dysfunction by Inhibiting Loss of Peritubular Capillaries and Tubulointerstitial Fibrosis in a Rat Model of Chronic Kidney Disease

“…After male Sprague-Dawley rats (200 to 250 g) underwent baseline measurement of BP and renal function, five-sixths subtotal nephrectomy (Nx; right nephrectomy with surgical resection of the lower and upper thirds of left kidney) was performed as described previously (10). Four weeks after Nx, BP was measured using a tail-cuff sphygmomanometer using an automated system with a photoelectric sensor (BP-98A; Softron, Tokyo, Japan), and blood and urine samples were collected.…”

“…Furthermore, plasma level of ADMA is known to be a strong predictor of the progression of renal dysfunction in patients with CKD (11,12). According to the recent comprehensive review on the potential role of ADMA in renal disease progression (13), there may be two major possible mechanisms by which ADMA could contribute to the progression of CKD; one is a BP-dependent effect of ADMA described previously (4,10), and the other is a BP-independent, direct effect of ADMA on renal microvasculature. As to the latter, Kang et al (14) demonstrated that administration of an inhibitor of NOS accelerated renal injury and impaired angiogenic response and peritubular capillary formation in the remnant kidney model, whose harmful effects were greater than expected from the increase in BP levels, thus suggesting that an important role of NO in maintaining renal microvasculature (15,16).…”

“…ADMA is mainly metabolized by an enzyme dimethylarginine dimethylaminohydrolase (DDAH) (1,2). We recently found that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of CKD (10). Furthermore, plasma level of ADMA is known to be a strong predictor of the progression of renal dysfunction in patients with CKD (11,12).…”