GW501516, a PPARd Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFkB Pathway in Mice.

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPAR&agr;, &dgr; and &ggr;. It has been demonstrated that PPAR&agr; and &ggr; agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPAR&dgr; agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPAR&dgr; agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(2). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNF&agr;. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNF&agr; is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNF&agr;- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-&bgr; activated kinase 1 (TAK1)-NFkB pathway, a common downstream signaling pathway to TNF&agr; receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases. [ABSTRACT FROM AUTHOR]