Role of PPARα and Its Agonist in Renal Diseases

Abstract

Peroxisome proliferator-activated receptor (PPAR)-α, a member of a large nuclear receptor superfamily, plays a major role in the regulation of lipid metabolism. Recently, PPARα activation has been shown to confer additional benefits on endothelial function, kidney function, and anti-inflammation, suggesting that PPARα agonists may be good candidates for treating acute renal failure. In clinical application, PPAR-α activators, such as hypolipidemic drugs in fibric acid class, were proven to have therapeutic effects on metabolic syndrome and cardiovascular disease. This paper focuses on signaling pathways, ligand selectivity, and physio-pathological roles of PPARα in kidney diseases and the therapeutic utility of PPARα modulators in the treatment of diabetes and inflammation-induced nephropathy. Implication of new and more potent PPAR-α activators could provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and the prevention of diabetic or inflammation-induced nephropathy in the future.

Figure 1

Schematic diagram presenting the signaling pathways of PPARα involved in the mechanisms of ischemic/reperfusion-, drugs-, or diabetic-induced renal damage. PPARα forms heterodimer with RXR. In the absence of ligands, the dimer may recruit a corepressor, inhibiting PPARα-mediated transcription of target genes. The presence of an agonist, or an activator such as PGI2, triggers the recruitment of a coactivator complex which induces transcriptional activity of PPARα onto its target genes. This leads to an increase in fatty acid catabolism and adenosine triphosphate (ATP) production, also to decrease the levels of cytotoxic fatty acid peroxidation (PO_x) products, and, consequently, to promote cell viability and inhibit renal epithelium cell death. In addition, PPARα complex can attenuate NFκB-induced inflammatory factors (IL-6, INFγ, or TNFα) induced by ischemic/reperfusion injury (I/R) or drugs. Furthermore, PPARα complex can inhibit masengial matrix proliferation induced by TGFβ or reactive oxidative stress (ROS) which then resulted in albuminuria. After SUMOylation of PPARα, SUMOylated PPARα resulted in downregulation of its transcriptional activity by promoting its interaction with the corepressor NCoR, which will compromise cell viability and activate cell death processes. CoAct, coactivator; DM, diabetes mellitus; FAO, fatty acid oxidation; FFA, free fatty acid; IFNγ, interferon γ; IL-6, interleukine-6; I/R, ischemia/reperfusion; NCoR, nuclear corepressor; NF-κB, nuclear factor-κB; PGI2, prostacyclin; POx, peroxidation; PPARα, peroxisome proliferator-activated receptor-α; RXR, retinoid X receptor; TGFβ, tumor growth factor β; TNFα, tumor necrosis factor α.