|
|
||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CALL FOR PAPERS
Aldosterone and Epithelial Na+ Channels
Fibrosis Research Laboratory, Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah
Submitted 10 January 2008 ; accepted in final form 21 March 2008
Aldosterone is thought to modulate renal fibrosis, in part, through increasing plasminogen activator inhibitor type 1 (PAI-1), a major inhibitor of ECM degradation. The present study investigated aldosterone effects on PAI-1 and transforming growth factor (TGF)-β1 and asked whether PAI-1 effects were TGF-β mediated and whether aldosterone and TGF-β1 acted synergistically to increase PAI-1 and decrease ECM degradation. Rat mesangial cells (MCs) and fibroblast cells [normal rat kidney (NRK)-49F] were used. 3H-labeled ECM was produced by MCs. The effect of aldosterone and TGF-β on ECM degradation by newly plated MCs or NRK-49F was measured by the release of 3H into medium. Aldosterone markedly increased PAI-1 mRNA and protein in both cell types, increases completely blocked by spironolactone and partially blocked by TGF-β neutralizing antibody. Adding both aldosterone and TGF-β1 produced PAI-1 mRNA and protein increases higher than the sum of increases seen with either compound alone. Aldosterone or TGF-β1 alone inhibited matrix degradation by 39 and 49% in MCs and 21 and 23% in NRK-49F, respectively. When both compounds were added, matrix degradation was further decreased by 93% in MCs and 61% in NRK-49F. The results indicate that aldosterone-induced PAI-1 increases are partially mediated by TGF-β1 and lead to decreased ECM degradation. While aldosterone alone induced TGF-β1 weakly, aldosterone and TGF-β1 added together produced dramatic synergistic effects on PAI-1 production and subsequent ECM accumulation. Thus the elevated aldosterone induced by renin-angiotensin-aldosterone system activation may amplify renin-angiotensin-aldosterone system profibrotic actions.
transforming growth factor-β; plasminogen activator inhibitor-1
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |