Journal
KIDNEY INTERNATIONAL
Volume 89, Issue 2, Pages 386-398Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.331
Keywords
diabetic nephropathy; gene therapy; oxidative stress; proximal tubule; TGF-beta
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Funding
- General Research Fund from the Research Grants Council of Hong Kong [HKU 779611M]
- National Basic Research Program of China 973 program [2012CB517600, 2012CB517606]
- Hong Kong Concrete
- Continental Cement and Gypsum Co. Ltd.
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Kallistatin 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.
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