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.

Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

“…38,39 Our recent study showed that high salt-induced kidney damage in KL(+/2) mice may involve activation of the MCP-1/CCR2 pathway and infiltration of T cells and macrophages. 16 Although we cannot exclude the contribution of hypertension to renal impairment in KL(+/2) mice, consistent results of other studies without the confounding interference of hypertension 7,40,41 suggest that the activated inflammatory process could play an independent and important role in renal damage.…”

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…[24][25][26][27][28] Importantly, the aldosterone-induced damage to the heart and kidneys is largely independent of the systemic effects on blood pressure. 10,29 Inflammation and fibrosis seem to play central roles in the pathophysiology of both cardiac and renal aldosteroneinduced injury. In response to treatment with aldosterone and salt, rat myocardium displays increased inflammation and upregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β1 (TGF-β).…”

“…31 These effects may be mediated by serum-and glucocorticoid-induced protein kinase-1 and transcription factors nuclear factor-κB and activator protein-1, the expression and activity of which, respectively, are stimulated by aldosterone/salt or angiotensin II/salt in animal heart and kidneys. [29][30][31][32][33] Kidney biopsies from patients with high albuminuria show significant increases in the expression of serum-and glucocorticoid-induced protein kinase-1 and the inflammatory mediators macrophage chemoattractant protein-1, TGF-β, and The direct deleterious effects of aldosterone/MR activation in the heart and kidneys and the common pathophysiological mechanisms involved. The benefits of MRAs in interrupting these pathways are also illustrated.…”

“…30,34,35 Aldosterone-induced oxidative and nitrosative stress has also been demonstrated in the rat kidney. 29 Increased oxidative stress, inflammation, and fibrosis are evident in several animal models of cardiac and renal diseases (eg, rats post-MI, dogs with HF, and uninephrectomized diabetic rats). 18,[38][39][40] Furthermore, MR activation stimulates apoptosis and causes vasoconstriction and reduced blood flow in the animal heart and kidneys.…”

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

“…Ald is associated with cellular oxidative stress, 7,8 inducing both glomerular and tubulointerstitial injury in the salt-sensitive hypertension model. [9][10][11][12] As tubulointerstitial damage is strongly associated with the prognosis of CKD, 13,14 a new strategy with antioxidant activity is needed for preventing the progression of such damage due to hypertension.…”