过氧化物酶体增殖物激活受体α（PPARα）在慢性肾脏疾病患者的肾脏中显著降低。纤维酸类（PPARα激动剂）是治疗高三酰甘油血症和潜在治疗CKD的药物。然而，常规纤维酸类药物因肾排泄而被消除，限制了其在肾功能受损患者中的应用。本研究旨在通过临床数据库分析评估常规纤维酸类药物与肾脏的风险并研究新型选择性PPARα调节剂pemafibrate的保肾作用。使用美国食品和药物管理局不良事件报告系统评估了常规纤维酸类药物（芬菲布拉特和倍他司酞）对肾脏的风险。使用口服导管每日管理pemafibrate（1或0.3毫克/千克/天）。在单侧输尿管梗阻（UUO）致肾纤维化小鼠（UUO小鼠）和腺嘌呤诱导的CKD模型小鼠（CKD小鼠）中检验其保肾作用。常规纤维酸类药物使用后，肾小球滤过率下降的比率和血清肌酐水平增加的比率显著增加。Pemafibrate管理抑制了UUO小鼠肾脏中胶原I、纤维连接蛋白和白细胞介素1β（IL-1β）基因表达的升高。在CKD小鼠中，它抑制了血清肌酐和血尿素氮增加以及红细胞计数、血红蛋白和红细胞比容水平的降低，还能够降低肾脏纤维化病变。此外，它还抑制了CKD小鼠肾脏中单核细胞趋化蛋白-1、IL-1β、肿瘤坏死因子α和IL-6的上调。这些结果证实了pemafibrate在CKD小鼠中的保肾作用，确认了它作为肾脏疾病治疗药物的潜力。版权所有©2023 Elsevier Inc.

Peroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile.The risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice).The ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1β) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1β, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice.These results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders.Copyright © 2023. Published by Elsevier Inc.