ADP-核糖基化因子鸟嘌呤核苷酸交换因子3通过抑制线粒体脂肪酸氧化，加剧顺铂诱导的急性肾损伤

Abstract

Acute kidney injury lacks definitive therapeutic options and clear molecular mechanisms. The proximal tubule demands high energy primarily derived from mitochondrial fatty acid beta-oxidation. ADP-ribosylation factor guanine nucleotide exchange factor 3 (Arfgef3) plays a role in tumor-associated diseases, but its function in nephrotoxicity remains unclear. We hypothesized that this exchange factor contributes to cisplatin-induced AKI by disrupting peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α)–mediated mitochondrial function and fatty acid oxidation. We utilized global knockout mice and human kidney 2 cells to investigate this exchange factor in cisplatin-induced injury in vivo and in vitro. Renal function was evaluated using biochemical markers and histopathological scores. Mitochondrial integrity and respiratory capacity were measured via transmission electron microscopy and Seahorse analysis. Intracellular lipid accumulation, key fatty acid oxidation enzymes, and physical interactions with PGC-1α were evaluated alongside small-molecule agonist rescue experiments. Arfgef3 was upregulated in renal tubular epithelial cells after cisplatin exposure. Genetic Arfgef3 knockout in mice significantly attenuated cisplatin-induced elevations in serum creatinine, blood urea nitrogen, tubular necrosis, inflammation, and cellular apoptosis. Furthermore, loss of this protein preserved mitochondrial ultrastructure, restored cellular adenosine triphosphate production, and reversed the suppression of key fatty acid oxidation enzymes. Mechanistically, co-immunoprecipitation confirmed a direct interaction between Arfgef3 and PGC-1α. Activating the coactivator with the agonist ZLN005 substantially rescued the aggravated mitochondrial damage and lipid accumulation caused by Arfgef3 overexpression. Arfgef3 promotes cisplatin-induced AKI through PGC-1α-mediated mitochondrial dysfunction and impaired fatty acid oxidation. Targeting this novel signaling path