Objective To explore the mechanism by which muscone improves cisplatin-induced acute kidney injury (AKI). Methods C57BL/6J mice were randomly divided into control group, model group, dexamethasone (2 mg/kg) group, muscone low-, medium-, and high-dose (24, 36, 48 mg/kg) groups, a cisplatin-induced AKI mouse model was established. After drug intervention, renal tissue pathological changes were observed using hematoxylin-eosin (HE) staining. Immunohistochemistry was used to detect the expressions and distribution of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) in kidney. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were detected. Immunofluorescence staining was used to detect the expression and distribution of cleaved cysteine aspartate protease-3 (cleaved Caspase-3) in renal tissue. An NRK-52E cell injury model induced by cisplatin was established, the effects of cisplatin, muscone and p53 inhibitor pifithrin-μ on cell viability were detected using MTT assay. The morphological change of cells was observed under an inverted microscope. Calcein AM/PI staining was used to observe cell death. Hoechest 33342 staining was used to observe the fragmentation of cell nuclei. Cell death types was observed using transmission electron microscopy. Immunofluorescence staining was used to detect the expression and distribution of p53. Western blotting was used to detect the expressions of Caspase-3, cleaved Caspase-3 and p53. MitoSOX staining was used to detect the levels of mitochondrial reactive oxygen species (mtROS). Immunoprecipitation was used to detect the level of p53 ubiquitination modification. Results Muscone significantly reduced the renal pathological damage caused by cisplatin, restored the morphology of renal tubules (P < 0.01), decreased the expressions and distribution of NGAL, Kim-1 and cleaved Caspase-3 in renal tissue (P < 0.01), reduced the levels of BUN and SCr (P < 0.01). Muscone and pifithrin-μ significantly inhibited cisplatin-induced apoptosis and mtROS level in NRK-52E cells (P < 0.01), upregulated Caspase-3 protein expression (P < 0.05, 0.01), downregulated cleaved Caspase-3 and p53 protein expressions (P < 0.05, 0.01), and promoted p53 ubiquitination modification (P < 0.05). Conclusion Muscone inhibits apoptosis of renal tubular epithelial cells by promoting p53 ubiquitination modification, thereby improving cisplatin-induced AKI.

muscone  /  cisplatin  /  p53  /  apoptosis  /  ubiquitination  /  acute kidney injury