Molecular mechanisms and therapeutic strategies of chronic renal injury: renoprotective effects of aldosterone blockade.
Recent clinical and pre-clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in renal injury. We have demonstrated in rats that chronic treatment with aldosterone results in severe proteinuria and renal injury, characterized by glomerular changes, tubulointerstitial fibrosis, and collagen accumulation. We also observed increased reactive oxygen species (ROS) generation and mitogen-activated protein kinases (MAPKs) activity in renal cortical tissues. Treatment with a selective MR antagonist, eplerenone, prevented elevation of ROS levels and MAPK activity, as well as ameliorating renal injury. In vitro studies revealed that MRs are highly expressed in rat glomerular mesangial cells (RMC) and rat renal fibroblasts. In RMC, aldosterone induces cellular injuries through NADPH oxidase-dependent ROS production and/or MAPK activation. Aldosterone-induced renal cellular injuries were markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent renal injury through mechanisms that cannot be simply explained by hemodynamic changes. In this review, we summarized our recent findings pertaining to the roles of aldosterone and MRs in the pathogenesis of renal injury. Potential molecular mechanisms responsible for aldosterone/MR-induced renal injury were also discussed.
Nishiyama
Akira
A
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan. akira@kms.ac.jp
Abe
Youichi
Y
D000450:Aldosterone / Q000633:toxicity; D000818:Animals; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000077545:Eplerenone; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases