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Article: Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress

TitleKallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress
Authors
Issue Date2016
Citation
Kidney International, 2016, v. 89 n. 2, p. 386-398 How to Cite?
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-kappaB 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.Kidney International advance online publication, 4 November 2015; doi:10.1038/ki.2015.331.
Persistent Identifierhttp://hdl.handle.net/10722/227371
ISSN

 

DC FieldValueLanguage
dc.contributor.authorYiu, WH-
dc.contributor.authorWong, WLD-
dc.contributor.authorWu, H-
dc.contributor.authorLi, R-
dc.contributor.authorYam, IYL-
dc.contributor.authorChan, YY-
dc.contributor.authorLeung, JCK-
dc.contributor.authorLan, HY-
dc.contributor.authorLai, KN-
dc.contributor.authorTang, SCW-
dc.date.accessioned2016-07-18T09:10:04Z-
dc.date.available2016-07-18T09:10:04Z-
dc.date.issued2016-
dc.identifier.citationKidney International, 2016, v. 89 n. 2, p. 386-398-
dc.identifier.issn1523-1755 (Electronic) 0085-2538 (Linkin-
dc.identifier.urihttp://hdl.handle.net/10722/227371-
dc.description.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-kappaB 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.Kidney International advance online publication, 4 November 2015; doi:10.1038/ki.2015.331.-
dc.languageeng-
dc.relation.ispartofKidney International-
dc.titleKallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress-
dc.typeArticle-
dc.identifier.emailYiu, WH: whyiu@hku.hk-
dc.identifier.emailYam, IYL: iylyam@hkucc.hku.hk-
dc.identifier.emailChan, YY: yychanb@hku.hk-
dc.identifier.emailLeung, JCK: jckleung@hku.hk-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailTang, SCW: scwtang@hku.hk-
dc.identifier.authorityLeung, JCK=rp00448-
dc.identifier.authorityLai, KN=rp00324-
dc.identifier.authorityTang, SCW=rp00480-
dc.identifier.doi10.1038/ki.2015.331-
dc.identifier.hkuros259637-

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