Protective Effects of Pemafibrate against Ischemia-Reperfusion-Induced AKI in Mice

Background: The effect of peroxisome proliferator-activated receptor alpha (PPARα) on acute kidney injury (AKI) is unknown due to the limited literature investigating the renoprotective effect of PPARα in AKI using fenofibrate. Pemafibrate, a novel PPARα modulator, is characterized by high selectivity for PPARα. In this study, we aimed to explore the function of PPARα using pemafibrate in renal ischemic injury. Methods: Twelve-week-old male C57BL/6J mice were divided into two groups: the pemafibrate group, which received mixed pemafibrate in their diet for 1 week before surgery, and the normal diet group. Bilateral 35-minute ischemia-reperfusion (I/R) was performed on the mice to produce an ischemic AKI model (n=9 in both groups). A sham operation was also performed for control (n=3 in each group). All mice were sacrificed 24 hours after I/R or sham operation. Renal function, histology, and tissue gene expression were evaluated. Results: Serum creatinine levels were significantly lower in the pemafibrate group than in the normal diet group. Pathological findings showed mild expansion of the urinary tubule lumen and slight loss of the brush border in the pemafibrate group compared to the normal diet group. RNA analyses revealed decreased expressions of urinary tubule injury markers and inflammatory genes. The renal PPARα expression was not significantly different between groups. However, oil red O staining showed less fat droplet accumulation, and the gene expressions of enzymes involved in fatty acid oxidation and anti-oxidative stress, which are target genes of PPARα, were up-regulated in the pemafibrate group. Conclusion: Pemafibrate treatment attenuated ischemic AKI by activating fatty acid metabolism and reducing oxidative stress.