Abstract | BACKGROUND: METHODS: Recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) was intravenously administrated to diabetic rats. Three days after the treatment, effects of DDAH overexpression on plasma or urinary levels of ADMA or NO metabolites (NOx), tubulointerstitial ischaemia and renal expression of transforming growth factor-beta ( TGF-beta) were evaluated. RESULTS: Renal DDAH expression and activity were reduced in diabetic rats. Urinary levels of ADMA and TGF-beta were increased, while NOx levels were decreased in diabetic rats. Compared with control rats, pimonidazole-detected hypoxic areas were larger in the kidney of diabetic rats, although the number of capillaries in tubulointerstitial regions was not different between the two groups. In addition, renal expression levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and TGF-beta were also increased in diabetic rats. DDAH overexpression significantly inhibited the increase of ADMA and the decrease of NOx and subsequently decreased urinary albumin excretion levels and ameliorated tubulointerstitial hypoxia and HIF-1alpha as well as TGF-beta expression in diabetic rats. CONCLUSION: The present study demonstrated for the first time that the suppression of ADMA by DDAH overexpression could improve tubulointerstitial ischaemia and subsequent renal damage in experimental diabetic nephropathy. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of early diabetic nephropathy.
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Authors | Ryo Shibata, Seiji Ueda, Sho-Ichi Yamagishi, Yusuke Kaida, Yuriko Matsumoto, Kei Fukami, Ayako Hayashida, Hidehiro Matsuoka, Seiya Kato, Masumi Kimoto, Seiya Okuda |
Journal | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
(Nephrol Dial Transplant)
Vol. 24
Issue 4
Pg. 1162-9
(Apr 2009)
ISSN: 1460-2385 [Electronic] England |
PMID | 19015171
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Nitric Oxide
- N,N-dimethylarginine
- Arginine
- Amidohydrolases
- dimethylargininase
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Topics |
- Adenoviridae
- Amidohydrolases
(biosynthesis)
- Animals
- Arginine
(analogs & derivatives, antagonists & inhibitors, physiology)
- Diabetic Nephropathies
(physiopathology)
- Disease Models, Animal
- Genetic Vectors
- Ischemia
(physiopathology)
- Kidney
(blood supply)
- Male
- Nephritis, Interstitial
(physiopathology)
- Nitric Oxide
(antagonists & inhibitors)
- Rats
- Rats, Sprague-Dawley
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