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Aldosterone and Epithelial Na⁺ Channels

Aldosterone and TGF-β₁ synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

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