Buspirone attenuates cyclophosphamide-induced renal dysfunction in association with alterations in miR-205/EGLN2, Nrf2, and PERK/ATF4/CHOP signaling
Although microRNAs have been investigated, the reno-protective role of microRNA-205 (miR-205) in cyclophosphamide (CPA)-induced nephrotoxicity has not yet been explored. Therefore, this study evaluated the influence of buspirone on miR-205 and its downstream target EGLN2, focusing on oxidative and ER stress as key drivers of renal injury. This represents a significant gap in nephrotoxicology and epigenetic Toxicology research. Animals were randomly allocated among four groups (n = 8), including the normal control group and the CPA group that received one intraperitoneal injection of CPA at 200 mg/kg on day 7. Buspirone at 5 or 10 mg/kg per day was administered by oral gavage for ten consecutive days, whereas CPA injected on the seventh day. At experimental completion, blood samples and renal tissues were subjected to analysis using biochemical, histopathological, immunohistochemical, Western blotting, and qRT-PCR techniques. CPA induced marked renal dysfunction, reflected by elevated SCr, BUN, NGAL, and KIM-1, with evident histopathological damage. This was accompanied by miR-205 suppression, EGLN2 upregulation, impaired Nrf2 signaling, increased PC levels, and stimulation of PERK/eIF2α/ATF4/CHOP-linked ER stress signaling ( p < 0.01). Concurrently, activation of JNK1, Fos, and NF-κB increased inflammatory cytokines, and initiated caspase-dependent apoptotic signaling ( p < 0.01). Buspirone pretreatment mitigated these alterations, accompanied by increased miR-205 expression, reduced EGLN2 expression, enhanced Nrf2-associated antioxidant defenses, and attenuation of ER stress, inflammation, and apoptosis, thereby preserving renal function and tissue integrity. These findings highlight the preventive renoprotective potential of buspirone against CPA-induced nephrotoxicity and underscore the relevance of miR-205/EGLN2 signaling in renal stress responses. Future toxicokinetic and toxicodynamic studies should evaluate buspirone’s safety in tumor treatment.