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


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.
Department of Pharmacology, University Health Sciences Center, Louisiana, USA.
Kazi
K
Rafiq
Daisuke
D
Nakano
Genei
G
Ihara
Hirofumi
H
Hitomi
Yoshihide
Y
Fujisawa
Naro
N
Ohashi
Hiroyuki
H
Kobori
Yukiko
Y
Nagai
Hideyasu
H
Kiyomoto
Masakazu
M
Kohno
Akira
A
Nishiyama
D000315:Adrenalectomy; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000633:toxicity; D000077545:Eplerenone; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity*; D006854:Hydrocortisone / Q000633:toxicity*; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D017931:DNA Primers; D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D003907:Dexamethasone; D006854:Hydrocortisone
Curr Opin Nephrol Hypertens. 2005 Jan;14(1):59-66
15586017
Hypertension. 2009 Oct;54(4):890-6
19635986
J Hypertens. 1988 Jan;6(1):25-31
2965178
Reprod Toxicol. 2009 Jul;28(1):46-51
19490994
Kidney Int. 2003 May;63(5):1791-800
12675855
Pancreas. 1988;3(4):459-64
3050978
J Am Soc Nephrol. 2008 Oct;19(10):1975-81
18667732
Clin Exp Pharmacol Physiol. 2008 Apr;35(4):477-82
18307745
Mol Cell Biol. 2002 Jun;22(11):3698-706
11997506
J Hypertens. 1989 Jul;7(7):537-49
2760458
EMBO J. 1999 Jun 1;18(11):3024-33
10357815
Nihon Yakurigaku Zasshi. 2004 Aug;124(2):101-9
15277728
Heart Fail Rev. 2005 Jan;10(1):15-22
15947887
Hypertension. 2003 May;41(5):1021-6
12682082
Mol Cell Endocrinol. 2003 Feb 28;200(1-2):45-55
12644298
Clin Endocrinol (Oxf). 2000 Mar;52(3):349-53
10718833
Hypertension. 2005 Apr;45(4):710-6
15699469
Am J Physiol Renal Physiol. 2009 Sep;297(3):F802-8
19535572
Exp Cell Res. 2008 Dec 10;314(20):3654-62
18929559
Science. 1988 Oct 28;242(4878):583-5
2845584
Diabetologia. 2008 Sep;51(9):1741-51
18636238
Clin Exp Nephrol. 2008 Aug;12(4):233-242
18317876
Hypertension. 2006 Jun;47(6):1084-93
16636193
Mol Endocrinol. 2005 Jun;19(6):1460-73
15761029
Clin Exp Hypertens. 1994 Nov;16(6):761-78
7858558
Clin Exp Pharmacol Physiol. 2008 Aug;35(8):922-7
18430060
Endocrinology. 1996 Dec;137(12):5264-8
8940344
J Am Soc Nephrol. 2005 Aug;16(8):2296-305
15975997
Best Pract Res Clin Endocrinol Metab. 2003 Dec;17(4):575-89
14687590
Clin Exp Pharmacol Physiol. 2010 Mar;37(3):277-82
19769609
Nephrol Dial Transplant. 2007 May;22(5):1314-22
17324946
Hypertension. 2007 Feb;49(2):355-64
17200434
Hypertension. 1998 Jan;31(1 Pt 2):451-8
9453344
Hypertension. 2004 Apr;43(4):841-8
14769808
Am J Pathol. 2006 Mar;168(3):737-47
16507889
J Am Soc Nephrol. 2005 Mar;16(3):703-11
15647337
Kidney Int. 2006 Dec;70(12):2116-23
17035949