Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy.
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 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.


CONCLUSIONS
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.
Shibata
Ryo
R
Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Ueda
Seiji
S
Yamagishi
Sho-Ichi
S
Kaida
Yusuke
Y
Matsumoto
Yuriko
Y
Fukami
Kei
K
Hayashida
Ayako
A
Matsuoka
Hidehiro
H
Kato
Seiya
S
Kimoto
Masumi
M
Okuda
Seiya
S
D000256:Adenoviridae; D000581:Amidohydrolases / Q000096:biosynthesis; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000502:physiology; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D007511:Ischemia / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009395:Nephritis, Interstitial / Q000503:physiopathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase