PPARα/β Activation Alleviates Age-Associated Renal Fibrosis in Sprague Dawley Rats

Age-associated renal fibrosis is commonly observed, with a decline in renal function during aging. Although peroxisome proliferator-activated receptors alpha/beta (PPAR alpha/beta) activation has been shown to exert beneficial effects on age-associated renal changes, its effects on age-associated renal fibrosis have not been investigated yet. Here, we show that the PPAR alpha/beta activator, MHY2013, can significantly alter lipid metabolism in renal tubule epithelial cells and attenuate renal fibrosis in aged Sprague Dawley (SD) rats. We found that MHY2013 significantly increased nuclear translocation and activity of PPAR alpha/beta in NRK52E renal epithelial cells. Moreover, the enhanced PPAR alpha/beta activity increased the expression of fatty acid oxidation-associated PPAR alpha/beta target genes. In addition, transforming growth factor-beta (TGF-beta)- and oleic acid-induced lipid accumulation and fibrosis-associated gene expression were decreased in NRK52E cells by MHY2013 pretreatment. To evaluate the effects of MHY2013 on age-associated renal fibrosis, aged SD rates were orally administered MHY2013 (1 and 5 mg/kg) daily for 1 month. MHY2013 efficiently increased PPAR alpha/beta activation and reduced renal lipid accumulation in aged SD rat kidneys. Furthermore, renal fibrosis was significantly decreased by MHY2013, indicating the importance of renal lipid metabolism in age-associated renal fibrosis. Taken together, our results suggest that activation of PPAR alpha/beta signaling during aging prevents age-associated renal fibrosis.