Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease
| Autor: | Seiji Ueda, Kei Fukami, Tsutomu Imaizumi, Hidehiro Matsuoka, Yuriko Matsumoto, Kyoko Matsuguma, Sho-ichi Yamagishi, Seiya Okuda, Ryo Shibata |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Nephrology
Male medicine.medical_specialty Renal function Arginine Kidney Peritubular capillaries Gene Expression Regulation Enzymologic Amidohydrolases Rats Sprague-Dawley chemistry.chemical_compound Fibrosis Transforming Growth Factor beta Internal medicine medicine Animals business.industry General Medicine Genetic Therapy medicine.disease Dimethylargininase Capillaries Rats Disease Models Animal Endocrinology medicine.anatomical_structure chemistry Chronic Disease Tubulointerstitial fibrosis Disease Progression Kidney Diseases business Asymmetric dimethylarginine Kidney disease |
| Zdroj: | Journal of the American Society of Nephrology : JASN. 18(5) |
| ISSN: | 1046-6673 |
| Popis: | 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 beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ-or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby 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. |
| Databáze: | OpenAIRE |
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