Impairment of PPAR{alpha} and the Fatty Acid Oxidation Pathway Aggravates Renal Fibrosis during Aging

In this study, we investigated peroxisome proliferator–activated receptor α (PPARα) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPARα and the FAO pathway–associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPARα protein expression associated with increased expression of PPARα-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPARα expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF-β–induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPARα–/– mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPARα signaling during aging aggravates renal fibrosis development, and targeting PPARα is useful for preventing age-a...
Source: Journal of the American Society of Nephrology : JASN - Category: Urology & Nephrology Authors: Tags: Basic Research Source Type: research