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Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats.

ABSTRACT: OBJECTIVES:Aldosterone is well recognized as the selective physiological ligand for mineralocorticoid receptor in epithelia. However, in-vitro studies have demonstrated that the affinity of aldosterone and glucocorticoids for mineralocorticoid receptor is similar. We hypothesized that glucocorticoids are involved in the development of renal injury through an mineralocorticoid receptor-dependent mechanism. METHODS AND RESULTS:Uninephrectomized (UNX) rats were treated with 1% NaCl and divided into three groups: vehicle, bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO; 5 mg/kg/day, s.c.), ADX + HYDRO + eplerenone (0.125% in chow). HYDRO-treated UNX-ADX rats showed increased blood pressure and urinary albumin-to-creatinine ratio with an increase in the expression of the mineralocorticoid receptor target genes, serum and glucocorticoid-regulated kinases-1 and Na+/H+ exchanger isoform-1, in renal tissues. HYDRO treatment induced morphological changes in the kidney, including glomerulosclerosis and podocyte injury. Treatment with eplerenone markedly decreased the gene expression and reduced the albuminuria and renal morphological changes. In contrast, dexamethasone (0.2 mg/kg per day, s.c.) + UNX + ADX induced hypertension and albuminuria in different groups of rats. Eplerenone failed to ameliorate these changes. CONCLUSIONS:Our findings indicate that chronic glucocorticoid excess could activate mineralocorticoid receptor and, in turn, induce the development of renal injury.

SUBMITTER: Rafiq K

PROVIDER: S-EPMC3034279 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats.

Rafiq Kazi K Nakano Daisuke D Ihara Genei G Hitomi Hirofumi H Fujisawa Yoshihide Y Ohashi Naro N Kobori Hiroyuki H Nagai Yukiko Y Kiyomoto Hideyasu H Kohno Masakazu M Nishiyama Akira A

Journal of hypertension 20110201 2

<h4>Objectives</h4>Aldosterone is well recognized as the selective physiological ligand for mineralocorticoid receptor in epithelia. However, in-vitro studies have demonstrated that the affinity of aldosterone and glucocorticoids for mineralocorticoid receptor is similar. We hypothesized that glucocorticoids are involved in the development of renal injury through an mineralocorticoid receptor-dependent mechanism.<h4>Methods and results</h4>Uninephrectomized (UNX) rats were treated with 1% NaCl a ...[more]

PMID: 21243738

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Project description:BackgroundObstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.MethodsMale Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.ResultsCB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.ConclusionCIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.

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Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats.

Publications

Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats.

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