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Published on: May 6, 2018
Sophoridine induces parthanatos in mouse renal tubular epithelial cells via mitochondrial dysfunction and
Fangyun Shi1, Jingduo Gao2, Baoyu Zhao3
1Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Abstract:
Sophoridine, a quinolizidine alkaloid from Sophora flavescens, shows therapeutic promise but its nephrotoxicity is poorly understood. This study investigated sophoridine-induced renal toxicity and its mechanisms in vivo (C57BL/6 mice, 45 mg/kg daily i.p. for 30 days) and in vitro (TCMK-1 renal tubular epithelial cells, 0-1.5 mg/mL). Subacute exposure caused severe tubular damage, elevated serum urea nitrogen and creatinine, and widespread downregulation of renal metabolic pathways. Mechanistically, sophoridine induced reactive oxygen species accumulation, ATP depletion, and mitochondrial membrane potential collapse, leading to nuclear translocation of apoptosis-inducing factor (AIF) without activating canonical caspase-dependent apoptosis. This identifies parthanatos, a caspase-independent, PARP-1/AIF-mediated programmed cell death pathway, as the mechanism underlying sophoridine-induced nephrotoxicity. AIF nuclear translocation was confirmed in mouse renal tissues. These findings reveal a novel toxic mechanism for sophoridine and identify the PARP-1/AIF axis as a potential target for mitigating alkaloid-induced renal injury.
