title: Osteopontin deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney.
abstract: Osteopontin (OPN) has been implicated in the pathology of several renal conditions. Recently, we demonstrated in vitro that aldosterone has important roles in collagen synthesis by inducing OPN (Irita J, Okura T, Kurata M, Miyoshi K, Fukuoka T, Higaki J. Hypertension 51: 507-513, 2008). The aim of the present study was to clarify the roles of OPN in aldosterone-mediated renal fibrosis by infusing aldosterone into either wild-type (WT) or OPN knockout mice (OPN(-/-)). We used uninephrectomized mice treated with aldosterone and high salt to exacerbate renal fibrosis. After 4 wk of treatment with aldosterone, we showed similar increases in systolic blood pressure in both strains of mice. Urine albumin excretion was greater in aldosterone-infused WT mice than in aldosterone-infused OPN(-/-) mice. Immunohistochemical analysis showed high levels of OPN expression in aldosterone-infused WT mice. Interstitial fibrosis and inflammatory infiltrations were increased in aldosterone-infused WT mice compared with either vehicle-infused WT or aldosterone-infused OPN(-/-) mice. These changes were ameliorated markedly by eplerenone treatment in aldosterone-infused WT mice. Aldosterone-infused WT mice also had increased expression of NADPH oxidase subunits compared with aldosterone-infused OPN(-/-) mice. We observed a marked increase in oxidative stress markers in aldosterone-infused WT mice compared with aldosterone-infused OPN(-/-) mice. These results indicate that OPN is a promoter of aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney and suggest that inhibition of OPN may be a potential therapeutic target for prevention of renal injury.
authors: Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Jun
authors: J
authors: Irita
authors: Takafumi
authors: T
authors: Okura
authors: Masanori
authors: M
authors: Jotoku
authors: Tomoaki
authors: T
authors: Nagao
authors: Daijiro
authors: D
authors: Enomoto
authors: Mie
authors: M
authors: Kurata
authors: Veena Rasika
authors: VR
authors: Desilva
authors: Ken-Ichi
authors: K
authors: Miyoshi
authors: Yutaka
authors: Y
authors: Matsui
authors: Toshimitsu
authors: T
authors: Uede
authors: David T
authors: DT
authors: Denhardt
authors: Susan R
authors: SR
authors: Rittiling
authors: Jitsuo
authors: J
authors: Higaki
mesh_terms: D000419:Albuminuria / Q000235:genetics; D000450:Aldosterone / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077545:Eplerenone; D005355:Fibrosis; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D053495:Osteopontin / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D017673:Sodium Chloride, Dietary; D053495:Osteopontin; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone