Pemafibrate Protects against Fatty Acid-Induced Nephropathy by Maintaining Renal Fatty Acid Metabolism

Abstract

As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.