Klotho and Peroxisome Proliferator-Activated Receptor Agonists Shows Synergistic Anti-fibrotic Effects on the Mouse Glomerular Mesangial Cells Stimulated by Transforming Growth Factor β

초록

Background: Klotho mainly expressed in the renal distal tubule is a trans-membrane protein and acts as co-receptor for fibroblast-growth factor 23. It is originally reported as an anti-aging protein and also correlate with an anti-inflammatory and anti-fibrotic function. Klotho is a target molecule of peroxisome proliferator-activated receptor γ (PPAR γ) which also has an anti-inflammatory and anti-fibrotic effects. In this study, we investigated whether Klotho and PPAR agonist had anti fibrotic effects and interactions of these two molecules on the transforming growth factor β (TGFβ) stimulated glomerular mesangial cells. Methods: Mouse glomerular mesangial cells stimulated by TGFβ were treated with AZ242 (PPARα/γ dual agonist), pioglitazone (PPAR γ agonist), Klotho, AZ242 + Klotho, pioglitazone + Klotho for 4 hours. Western blots for TGFβ1, PAI-1, phosphorylated Smad2 (pSmad2), PPAR γ, and Klotho were performed. Results: Klotho and PPAR γ protein expression were increased in all treated groups compared to TGFβ stimulated group (control group). PAI-1 expression was decreased in the AZ242 treated group and pioglitazone + Klotho treated group compared to control group. However, other treated groups showed no difference compared to control group. pSmad2 expression was markedly decreased in the AZ242 + Klotho treated group. Other treated groups revealed no difference of pSmad 2 expression compared to control group. TGFβ expression was decreased in the AZ242 + Klotho group and pioglitazone + Klotho group. Conclusions: Our results suggest that Klotho and PPAR agonists have interaction each other and shows synergistic anti-fibrotic effects on the TGFβ stimulated mouse glomerular mesangial cells.