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Background: Asymmetric dimethylarginine (ADMA) plays important roles in the pathogenesis of chronic kidney disease (CKD). We have recently found that ADMA is involved in glomerular sclerosis and tubulointerstitial fibrosis in an animal model of CKD. However, relationship between plasma ADMA levels and severity of renal damage in CKD patients remains unknown. Methods: Relatively young 109 biopsy-proven IgA nephropathy (IgAN) patients (age: 32.7 ± 13.2; estimated glomerular filtration rate, eGFR: 86.5 ± 28.8 ml/min/1.73 m2) were enrolled. We retrospectively investigated whether plasma levels of ADMA were associated with severity of the renal tissue damage and could be a predictor of the disease progression in our subjects. Results: ADMA levels were higher in IgAN patients than age-, sex- and mean eGFR-matched healthy volunteers (0.53 ± 0.14 vs. 0.43 ± 0.08 µM, p < 0.01). ADMA levels were associated with the severity of glomerular and tubulointerstitial injury. Multiple stepwise regression analysis revealed that ADMA, but not proteinuria was an independent determinant for the disease progression assessed by annual reduction rates of eGFR. In univariate analyses, ADMA levels were correlated with proteinuria, total cholesterol, triglycerides, and uric acid. Proteinuria was a sole independent correlate of ADMA in multiple stepwise regression analysis. Conclusion: The present study demonstrated that ADMA was correlated with the severity of the renal tissue damage and could be a predictor of disease progression in IgAN patients.

Aims Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been reported to be a novel marker for the progression of chronic kidney disease (CKD). We have recently found that accumulation of ADMA could trigger peritubular capillary loss, thus contributing to tubulointerstitial ischemia and fibrosis in a rat model of CKD. However, effects of ADMA on glomerular capillary loss and sclerosis remain to be elucidated. Main methods In this study, we investigated whether lowering of ADMA by overexpression of dimethylarginine dimethylaminohydrolase (DDAH), a main enzyme that degrades ADMA, could ameliorate glomerular capillary loss and sclerosis in a rat model of CKD. Four weeks after 5/6 subtotal nephrectomy (Nx), animals were given tail vein injections with recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial β-galactosidase (Adv-LZ), or orally administered with 20 mg/kg/day of hydralazine (Hyz) which served as a blood pressure control model. Key findings Plasma levels of ADMA were associated with decreased number of glomerular capillaries as well as severity of glomerular sclerosis in Nx-rats. These glomerular changes progressed in Adv-LZ- or Hyz-treated Nx-rats, while they were ameliorated by the treatment with DDAH overexpression. Significance Our present data suggest that ADMA may be involved in glomerular capillary loss and sclerosis, thus contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.