Osteopontin modulates angiotensin II-induced inflammation, oxidative stress, and fibrosis of the kidney.
Osteopontin, a secreted glycoprotein has been implicated in several renal pathological conditions such as those due to ureteral obstruction, ischemia, and cyclosporine toxicity. We studied its possible role in angiotensin II-mediated renal injury by infusing wild-type and osteopontin knockout mice with angiotensin II and found that it raised blood pressure and increased urinary albumin/creatinine ratios in both strains of mice. However, while wild-type mice responded to the infusion by macrophage infiltration and increased expression of alpha-smooth muscle actin, fibronectin, and transforming growth factor-beta; the osteopontin knockout mice developed none of these. Further, the knockout mice had increased expression of monocyte chemoattractant protein-1; NADPH oxidase subunits such as NOX2, gp47phox, and NOX4; and plasminogen activator inhibitor-1 compared to the wild type animals. Proximal tubule epithelial cells in culture treated with recombinant osteopontin and angiotensin II had increased alpha-smooth muscle actin and transforming growth factor-beta expression. The effect of angiotensin II was blocked by an antibody to osteopontin. In addition, osteopontin attenuated angiotensin II-induced plasminogen activator inhibitor-1 expression. These studies show that osteopontin is a promoter and an inhibitor of inflammation, oxidative stress, and fibrosis that is capable of modulating angiotensin II-induced renal damage.
Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Talya
T
Wolak
HyunJu
H
Kim
Yuelan
Y
Ren
Jason
J
Kim
Nosratola D
ND
Vaziri
Susanne B
SB
Nicholas
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D005355:Fibrosis; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*
D053495:Osteopontin; D000804:Angiotensin II