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

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 a...