Kidney fibrosis in hypertensive rats: role of oxidative stress.
Fibrosis of the glomerulus and the tubulointerstitium occurs in patients with hypertension. Studies have shown that renal oxidative stress appears in hypertensive kidney disease. The potential role of oxidative stress in renal fibrogenesis remains to be elucidated. Herein, we tested the hypothesis that oxidative stress contributes to the development of renal fibrosis during hypertension.Sprague-Dawley rats received angiotensin II (AngII; 9 microg/h s.c.) for 4 weeks with/without co-treatment of antioxidants, apocynin and tempol (120 mg/kg/day each, p.o.). Untreated rats served as controls. Appearance of renal oxidative stress and its effect on the expression of transforming growth factor (TGF)-beta(1), population of myofibroblasts, collagen synthesis/degradation and fibrosis in kidneys were examined. Chronic AngII infusion elevated systemic blood pressure (228 +/- 6 mm Hg), which was accompanied with extensive renal fibrosis and oxidative stress represented as upregulated NADPH oxidase and suppressed superoxide dismutase (SOD). Co-treatment with antioxidants led to: (1) markedly decreased renal NADPH oxidase; (2) significantly attenuated gene expression of TGF-beta(1), type I collagen, and tissue inhibitors of matrix metalloproteinase (TIMP)-I/-II in the kidney; (3) largely reduced population of myofibroblasts in both the cortex and medulla; (4) significantly reduced renal collagen volume, and (5) partially suppressed blood pressure (190 +/- 8 mm Hg). Thus, prolonged AngII administration promotes renal oxidative stress, which is associated with hypertensive renal disease. AngII induces renal oxidative stress by increasing NADPH oxidase and reducing SOD in the kidney, which, in turn, upregulates collagen synthesis, while suppressing collagen degradation, thereby promoting the development of fibrosis in kidneys of hypertensive rats.
Zhao
Wenyuan
W
Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tenn 38163, USA.
Chen
Sue S
SS
Chen
Yuanjian
Y
Ahokas
Robert A
RA
Sun
Yao
Y
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006973:Hypertension / Q000473:pathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009210:Myofibrils / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000235:genetics; D015854:Up-Regulation
D000975:Antioxidants; D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D003094:Collagen; D013482:Superoxide Dismutase; D019255:NADPH Oxidases