Peroxisome Proliferator-Activated Receptor Delta Protects against Obesity-Related Glomerulopathy through the P38 MAPK Pathway

Objective: Obesity is a prominent component of metabolic syndrome and a major risk factor for renal disease. The aim of this study was to explore the effect of cross-talk between peroxisome proliferator-activated receptor (PPAR)delta and p38 mitogen-activated protein kinase (p38 MAPK) on obesity-related glomerulopathy. Design and Methods: Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet for 32 weeks. Glomerular mesangial cells HBZY-1 and mature differentiation 3T3-L1 cells were cocultured and were transfected with PPAR delta-expressing vectors or treated with agonist or inhibitor of PPAR delta or p38 MAPK. Results: Rats on a high-fat diet showed typical characteristics of metabolic syndrome including obesity, dyslipidemia, insulin resistance, and hypertension. Rats on a high-fat diet also had significant glomerular hypertrophy and extracellular matrix accumulation, which were accompanied by increased p38 MAPK phosphorylation and decreased PPAR delta expression in the kidney tissue. The roles of p38 MAPK and PPAR delta in a coculture system of mesangial cells and mature differentiation 3T3-L1 cells were further explored. PPAR delta suppression promoted laminin and type IV collagen secretion through p38 MAPK phosphorylation in mesangial cells, whereas PPAR delta overexpression or PPAR delta agonist attenuated phosphorylation of p38 MAPK and laminin and type IV collagen secretion. Conclusions: The characteristics of obesity-related glomerulopathy, which might be partly caused by PPAR delta suppression-induced p38 MAPK activation and laminin and type IV collagen secretion was demonstrated.