Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress
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AbstractKallistatin is a serine protease inhibitor with anti-inflammatory, anti-angiogenic, and anti-oxidative properties. Since oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy, we studied the effect and mechanisms of action of kallistatin superinduction. Using ultrasound-microbubble-mediated gene transfer, kallistatin overexpression was induced in kidney tubules. In db/db mice, kallistatin overexpression reduced serum creatinine and BUN levels, ameliorated glomerulosclerosis and tubulointerstitial injury, and attenuated renal fibrosis by inhibiting TGF-beta signaling. Additionally, downstream PAI-1 and collagens I and IV expression were reduced and kallistatin partially suppressed renal inflammation by inhibiting NF-kappa B signaling and decreasing tissue kallikrein activity. Kallistatin lowered blood pressure and attenuated oxidative stress as evidenced by suppressed levels of NADPH oxidase 4, and oxidative markers (nitrotyrosine, 8-hydroxydeoxyguanosine, and malondialdehyde) in diabetic renal tissue. Kallistatin also inhibited RAGE expression in the diabetic kidney and AGE-stimulated cultured proximal tubular cells. Reduced AGE-induced reactive oxygen species generation reflected an anti oxidative mechanism via the AGE-RAGE-reactive oxygen species axis. These results indicate a renoprotective role of kallistatin against diabetic nephropathy by multiple mechanisms including suppression of oxidative stress, anti fibrotic and anti-inflammatory actions, and blood pressure lowering.
All Author(s) ListYiu WH, Wong DWL, Wu HJ, Li RX, Yam I, Chan LYY, Leung JCK, Lan HY, Lai KN, Tang SCW
Journal nameKidney International
Year2016
Month2
Day1
Volume Number89
Issue Number2
PublisherNATURE PUBLISHING GROUP
Pages386 - 398
ISSN0085-2538
eISSN1523-1755
LanguagesEnglish-United Kingdom
Keywordsdiabetic nephropathy; gene therapy; oxidative stress; proximal tubule; TGF-beta
Web of Science Subject CategoriesUrology & Nephrology

Last updated on 2021-21-02 at 01:12