Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11β-HSD activity.
Aldosterone (Aldo) can be a profibrotic factor in cardiovascular and renal tissues. This study tests the hypothesis that prolonged Aldo exposure is able to directly induce fibrotic changes in the kidney of a normal nonhypertensive animal. Immortalized rat proximal tubule cells (IRPTC) containing 11β-hydroxysteroid dehydrogenase (11β-HSD1) but no mineralocorticoid receptors (MR) and mouse inner medullary collecting duct cells (IMCD) containing 11β-HSD2 and MR were examined. IRPTC exposed to Aldo or corticosterone (10 nM) for 48 h demonstrated no change in collagen production as assessed by Sirius red staining. In contrast, IMCD treated with Aldo exhibited a marked increase in the expression of collagen, fibronectin, and connective tissue growth factor (CTGF), whereas corticosterone alone had no effect. The Aldo-induced overexperession of collagen, fibronectin, and CTGF was substantially attenuated by the MR antagonist RU-318 and by the 11β-HSD end product 11-dehydrocorticosterone, but not by the glucocorticoid receptor antagonist RU-486. In vivo, early fibrotic changes with elevated collagen, fibronectin, and CTGF expression were observed in kidneys isolated from normotensive adrenalectomized mice receiving a continuous infusion of Aldo (8 μg·kg(-1)·day(-1)) for 1 wk. These changes were not present in corticosterone-treated mice. Aldo-induced changes were attenuated in adrenally intact mice and in mice treated with RU-318 or 11-dehydrocorticosterone. Thus, extended Aldo exposure produces fibrotic changes in cells containing MR and in normal kidneys. MR antagonists and the end products of 11β-HSD attenuate these fibrogenic effects.
Brem
Andrew S
AS
Div. of Kidney Diseases and Hypertension, Rhode Island Hospital, Providence, RI 02903, USA.
Morris
David J
DJ
Ge
Yan
Y
Dworkin
Lance
L
Tolbert
Evelyn
E
Gong
Rujun
R
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism*; D000315:Adrenalectomy; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
D005353:Fibronectins; D018161:Receptors, Mineralocorticoid; D055513:Connective Tissue Growth Factor; D000450:Aldosterone; D003094:Collagen; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone