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

Kidney Int. 2016 Feb;89(2):386-98. doi: 10.1038/ki.2015.331.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Fibrosis
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Kallikreins / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Function Tests
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADPH Oxidase 4
  • NADPH Oxidases / metabolism
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Receptor for Advanced Glycation End Products / metabolism*
  • Serpins / physiology*
  • Transforming Growth Factor beta / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Ager protein, mouse
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptor for Advanced Glycation End Products
  • Serpins
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • kallistatin
  • 3-nitrotyrosine
  • Tyrosine
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • Kallikreins