Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

Am J Physiol Renal Physiol. 2012 Oct 15;303(8):F1230-8. doi: 10.1152/ajprenal.00257.2012. Epub 2012 Jul 18.


Kallistatin (KS) levels are reduced in the kidney and blood vessels under oxidative stress conditions. To determine the function of endogenous KS in the renal and cardiovascular systems, KS levels were depleted by daily injection of anti-rat KS antibody into DOCA-salt hypertensive rats for 10 days. Administration of anti-KS antibody resulted in reduced KS levels in the circulation but increased levels of serum thiobarbituric acid reactive substances (an indicator of lipid peroxidation) as well as superoxide formation in the aorta. Moreover, anti-KS antibody injection resulted in increased NADH oxidase activity and superoxide production but decreased nitric oxide levels in the kidney and heart. Endogenous KS blockade aggravated renal dysfunction, damage, hypertrophy, inflammation, and fibrosis as evidenced by decreased creatinine clearance and increased serum creatinine, blood urea nitrogen and urinary protein levels, tubular dilation, protein cast formation, glomerulosclerosis, glomerular enlargement, inflammatory cell accumulation, and collagen deposition. In addition, rats receiving anti-KS antibody had enhanced cardiac injury as indicated by cardiomyocyte hypertrophy, inflammation, myofibroblast accumulation, and fibrosis. Renal and cardiac injury caused by endogenous KS depletion was accompanied by increases in the expression of the proinflammatory genes tumor necrosis factor-α and intercellular adhesion molecule-1 and the profibrotic genes collagen I and III, transforming growth factor-β, and tissue inhibitor of metalloproteinase-1. Taken together, these results implicate an important role for endogenous KS in protection against salt-induced renal and cardiovascular injury in rats by suppressing oxidative stress, inflammation, hypertrophy, and fibrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Desoxycorticosterone / pharmacology
  • Hypertension / metabolism*
  • Hypertension / pathology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • Male
  • Multienzyme Complexes / metabolism
  • NADH, NADPH Oxidoreductases / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Rats
  • Rats, Wistar
  • Serpins / metabolism*
  • Sodium Chloride, Dietary / pharmacology
  • Superoxides / metabolism


  • Multienzyme Complexes
  • Serpins
  • Sodium Chloride, Dietary
  • kallistatin
  • Superoxides
  • Desoxycorticosterone
  • NADH oxidase
  • NADH, NADPH Oxidoreductases