Mineralocorticoid receptor blockade but not steroid withdrawal reverses renal fibrosis in deoxycorticosterone/salt rats.
The pathophysiologic effects of nonepithelial mineralocorticoid receptor (MR) activation include vascular inflammation followed by renal and cardiac remodeling in experimental animals. We have recently shown that MR blockade can reverse established cardiac fibrosis and vascular inflammation; the present study explores whether a similar protection is seen in renal tissue. Rats were uninephrectomized and maintained on 0.9% NaCl solution to drink and treated as follows: control, vehicle; deoxycorticosterone (DOC), 20 mg/wk sc for 4 wk and then killed; DOC for 8 wk; DOC for 4 wk and no steroid for wk 5-8; DOC for 8 wk and eplerenone 100 mg/kg.d in the food for wk 5-8. DOC increased renal collagen at 4 and 8 wk; rats given DOC for 4 wk and killed at 8 wk showed levels of fibrosis identical with those killed at 4 wk, whereas rats given DOC for 8 wk plus eplerenone for wk 5-8 were indistinguishable from control. The inflammatory markers ED-1, osteopontin, and cyclooxygenase-2 remained significantly elevated despite the withdrawal of DOC (DOC404), whereas eplerenone restored cyclooxygenase-2 expression (but not that of ED-1 or osteopontin) to control levels. In addition, markers of oxidative stress and TGFbeta were determined. We hypothesize that continuing tubular inflammation and fibrosis despite DOC withdrawal indicates that the renal tissue may reflect MR activation in the context of tissue damage.
Lam
Emily Y M
EY
Prince Henry's Institute of Medical Research, Endocrine Genetics, Clayton, Victoria 3168, Australia.
Funder
John W
JW
Nikolic-Paterson
David J
DJ
Fuller
Peter J
PJ
Young
Morag J
MJ
D000818:Animals; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005355:Fibrosis / Q000473:pathology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation; D007668:Kidney / Q000473:pathology*; D008297:Male; D053495:Osteopontin; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
D018161:Receptors, Mineralocorticoid; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D013256:Steroids; D053495:Osteopontin; D003900:Desoxycorticosterone; D003094:Collagen; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2