TY - JOUR
T1 - Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats
AU - Rafiq, Kazi
AU - Nakano, Daisuke
AU - Ihara, Genei
AU - Hitomi, Hirofumi
AU - Fujisawa, Yoshihide
AU - Ohashi, Naro
AU - Kobori, Hiroyuki
AU - Nagai, Yukiko
AU - Kiyomoto, Hideyasu
AU - Kohno, Masakazu
AU - Nishiyama, Akira
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - eplerenone
KW - hydrocortisone
KW - kidney diseases
KW - mineralocorticoid receptor
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U2 - 10.1097/HJH.0b013e32834103a9
DO - 10.1097/HJH.0b013e32834103a9
M3 - Article
C2 - 21243738
AN - SCOPUS:78651317494
VL - 29
SP - 290
EP - 298
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 2
ER -