PPAR α Activation Protects against Anti-Thy1 Nephritis by Suppressing Glomerular NF- κB Signaling

Abstract

The vast increase of chronic kidney disease (CKD) has attracted considerable attention worldwide, and the development of a novel therapeutic option against a representative kidney disease that leads to CKD, mesangial proliferative glomerulonephritis (MsPGN) would be significant. Peroxisome proliferator-activated receptor α (PPAR α), a member of the steroid/nuclear receptor superfamily, is known to perform various physiological functions. Recently, we reported that PPAR α in activated mesangial cells exerted anti-inflammatory effects and that the deficiency of PPAR α resulted in high susceptibility to glomerulonephritis. To investigate whether PPAR α activation improves the disease activity of MsPGN, we examined the protective effects of a PPAR α agonist, clofibrate, in a well-established model of human MsPGN, anti-Thy1 nephritis, for the first time. This study demonstrated that pretreatment with clofibrate (via a 0.02% or 0.1% clofibrate-containing diet) continuously activated the glomerular PPAR α, which outweighed the PPAR α deterioration associated with the nephritic process. The PPAR α activation appeared to suppress the NF- κB signaling pathway in glomeruli by the induction of I κB α, resulting in the reduction of proteinuria and the amelioration of the active inflammatory pathologic glomerular changes. These findings suggest the antinephritic potential of PPAR α-related medicines against MsPGN. PPAR α-related medicines might be useful as a treatment option for CKD.