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

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial ␤-galactosidase The synthesis of NO can be blocked by inhibition of the NOS active site with guanidino-substituted analogues of l-arginine, such as asymmetric dimethylarginine (ADMA) (1,2). We, along with others, have demonstrated that elevated plasma ADMA is associated with cardiovascular risk factors such as hypertension (3,4), diabetes (4,5), and chronic kidney disease (CKD) (6,7), thereby being one of the useful biomarkers for atherosclerosis and future cardiovascular events (5,7-9). 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). 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). Therefore, it is plausible that DDAH could protect against renal damage by suppressing the inhibitory effect of ADMA on NO generation. In this study, we investigated the effects of DDAH-elicited ADMA lowering on renal function and tubulointerstitial changes in a rat remnant kidney model. To address the issue of whether DDAH could protect against renal injury in a BPindependent manner, we compared the renoprotective effects of DDAH with those of hydralazine (Hyz), an antihypertensive drug with equihypotensive property.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

“…This finding is in line with recent observations by Matsumoto and colleagues (23) in which adenovirus-mediated overexpression of DDAH1 significantly reduced glomerular and interstitial fibrosis in subtotally nephrectomized rats. The infiltration of macrophages and T lymphocytes into the interstitium is a prominent finding and precedes interstitial fibrosis in ANG II-dependent forms of hypertension (17,21).…”

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

“…ADMA or L-NAME infusion into mice exacerbated renal fibrosis, but both raised SBP by approximately 60 mmHg, suggesting hypertensive injury 28 ; global DDAH1 overexpression, however, protected against fibrosis in angiotensin and surgical nephron-reduction models of CKD. 29,30 Genetic DDAH1 overexpression decreases circulating ADMA and introduces unmeasured effects upon normal regulatory mechanisms. Furthermore, DDAH1 overexpression occurs indiscriminately in cell types that do not normally express DDAH1, but play significant roles in inflammation and fibrosis (e.g., macrophages).…”

A New Perspective for the Treatment of Renal Diseases?

“…Therefore, lowering ADMA by increasing DDAH expression/activity might prevent progression in renal damage. Thus the study by Matsumoto et al represents an important proof of concept that lowering ADMA may retard renal disease progression (6). Preclinical studies with drugs that lower ADMA by increasing DDAH transcription have already been published (29), which may open an entirely new opportunity for the treatment of CV and renal disease.…”

“…Knowledge on ADMA has increased tremendously in recent years. Matsumoto et al now provide a new and decisive piece of information for deciphering the role of ADMA in renal disease progression, and their study will certainly attract investigators and resources into this very promising research area (6).…”

“…The last paper of this series, by Matsumoto et al (6), appears in this issue of JASN and provides perhaps decisive evidence on the causal role of ADMA in the progression of renal disease in the remnant kidney model (i.e., the model that is currently considered as the most representative of chronic kidney disease in humans) (4). Highlighting the key components influenced by the experimental maneuver adopted in this study-namely ADMA and dimethylarginine dimethylaminohydrolase (DDAH)-is crucial for framing the novel information provided by this groundbreaking study (6).…”