NDT Advance Access originally published online on November 17, 2008
Nephrology Dialysis Transplantation 2009 24(4):1162-1169; doi:10.1093/ndt/gfn630
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Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy
1 Division of Nephrology 2 Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume 3 Division of Pathology and Cell Biology, Graduate School and Faculty of Medicine, University of Ryukyus, Okinawa 4 Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Japan
Correspondence and offprint requests to: Seiji Ueda, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. Tel: +81-942-31-7763; Fax: +81-942-31-7002; E-mail: ueda{at}med.kurume-u.ac.jp
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Abstract |
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Background. Decreased peritubular capillary (PTC) flow due to impaired endothelial function elicits tubulointerstitial ischaemia, thereby enhancing renal damage in chronic kidney disease, including diabetic nephropathy. Since nitric oxide (NO) is a vasodilator and known to play an important role in the maintenance of PTC flow, it is conceivable that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may cause tubulointerstitial ischaemia, thus being involved in the progression of diabetic nephropathy. In this study, we investigated whether overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that degrades ADMA, could improve tubulointerstitial ischaemia in streptozotocin (STZ)-induced diabetic rats.
Methods. Recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial β-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-β (TGF-β) were evaluated.
Results. Renal DDAH expression and activity were reduced in diabetic rats. Urinary levels of ADMA and TGF-β 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-1
(HIF-1) and TGF-β 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-1 as well as TGF-β 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.
Keywords: asymmetric dimethylarginine; diabetic nephropathy; dimethylarginine dimethylaminohydrolase; endothelium; ischaemia
Received for publication: 8. 3.08
Accepted in revised form: 20.10.08