High-fat diet-induced renal cell apoptosis and oxidative stress in spontaneously hypertensive rat are ameliorated by fenofibrate through the PPARα-FoxO3a-PGC-1α pathway.

Background. The peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a lipid-sensing transcriptional factor that has a role in gluco-oxidative stress and lipotoxicity. Forkhead box O (FoxO)s and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha are also known to regulate cell metabolism, cell cycle arrest, apoptosis and oxidative stress during stressful conditions. We evaluated whether PPAR alpha-FoxOs-PGC-1 alpha signaling in overfed spontaneously hypertensive rats (SHR) has a protective role in the kidney. Methods. Male SHR and Wistar-Kyoto rats (WKY) fed a high-fat diet (HFD) received treatment with fenofibrate, PPAR alpha agonist or tempol, antioxidants for 12 weeks and were evaluated about the PPAR alpha-FoxOs-PGC-1 alpha pathway. Results. The SHRs with an HFD had an elevated systolic pressure, plasma insulin, free fatty acid (FFA) and triglyceride (TGs) levels, and they had induced glucose intolerance as well as albuminuria, glomerular expansion and renal inflammation. An HFD caused the accumulation of intra-renal FFA and TGs and this was related to a decrease in the PPAR alpha expression, the activation of phosphatidylinositol 3-kinase (PI3K)-Akt, phosphorylation of FoxO3a and decreases in the PGC-1 alpha and estrogen-related receptor (ERR)-1 alpha expressions, which suppressed the superoxide dismutase (SOD2) and Bcl-2 expressions and led to increases in oxidative stress and the number of apoptotic renal cells. Interestingly, administering fenofibrate or tempol to the HFD-induced SHRs reversed all of the renal phenotypes by increasing the PPAR alpha expression with concomitant inactivation of the PI3K-Akt pathway, dephosphorylation of FoxO3a and activation of PGC-1 alpha-ERR-1 alpha signaling, and this all resulted in ameliorating the oxidative stress and apoptotic cell death. Conclusion. Our results demonstrated that PPAR alpha agonists or antioxidants are associated with improvement of the circulating FFA and TGs levels and this prevents HFD-induced renal lipotoxicity and hypertension by the activation of PPAR alpha and its downstream signals of both FoxO3a and PGC-1 alpha.