title: Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress.
abstract: 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-β signaling. Additionally, downstream PAI-1 and collagens I and IV expression were reduced and kallistatin partially suppressed renal inflammation by inhibiting NF-κB 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.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.forename: Dickson W L
authors.initials: DW
authors.lastname: Wong
authors.forename: Hao Jia
authors.initials: HJ
authors.lastname: Wu
authors.forename: Rui Xi
authors.initials: RX
authors.lastname: Li
authors.forename: Irene
authors.initials: I
authors.lastname: Yam
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007610:Kallikreins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015843:Serpins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000593873:Ager protein, mouse; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D015843:Serpins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C051324:kallistatin; C002744:3-nitrotyrosine; D014443:Tyrosine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D007610:Kallikreins