CALL FOR PAPERS Aldosterone and Epithelial Na Channels Aldosterone and TGF- 1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

Huang W, Xu C, Kahng KW, Noble NA, Border WA, Huang Y. Aldosterone and TGF1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells. Am J Physiol Renal Physiol 294: F1287–F1295, 2008. First published March 26, 2008; doi:10.1152/ajprenal.00017.2008.—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)1 and asked whether PAI-1 effects were TGFmediated and whether aldosterone and TGF1 acted synergistically to increase PAI-1 and decrease ECM degradation. Rat mesangial cells (MCs) and fibroblast cells [normal rat kidney (NRK)-49F] were used. H-labeled ECM was produced by MCs. The effect of aldosterone and TGFon ECM degradation by newly plated MCs or NRK-49F was measured by the release of H into medium. Aldosterone markedly increased PAI-1 mRNA and protein in both cell types, increases completely blocked by spironolactone and partially blocked by TGFneutralizing antibody. Adding both aldosterone and TGF1 produced PAI-1 mRNA and protein increases higher than the sum of increases seen with either compound alone. Aldosterone or TGF1 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 TGF1 and lead to decreased ECM degradation. While aldosterone alone induced TGF1 weakly, aldosterone and TGF1 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.