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Abstract: TH-PO043

Effects of Paricalcitol on Ferroptosis in Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hu, Zhaoxin, Central South University, Changsha, China
  • Zhang, Wei, The Third Xiangya Hospital, Central South University, Changsha, China, Changsha, China
  • Zhang, Hao, The Third Xiangya Hospital, Central South University, Changsha, China, Changsha, China
Background

Ferroptosis is a newly defined form of non-apoptotic cell death characterized by the accumulation of iron-dependent membrane lipid peroxides. At present, ferroptosis is widely studied in rhabdomyolysis and ischemia/reperfusion-induced acute kidney injury (AKI), but the research on nephrotoxic AKI such as cisplatin is not deep enough. In this study, we explore whether ferroptosis occurs in cisplatin-induced AKI and the effect of paricalcitol on ferroptosis.

Methods

Twenty-five C57BL / 6 mice were randomly divided into control group, cisplatin + vehicle of Ferrostatin-1 (DMSO) group, cisplatin + Ferrostatin-1 (Fer-1) group, cisplatin + vehicle of paricalcitol (propylene glycol) group, cisplatin + paricalcitol group, 5 mice in each group. All drugs were injected intraperitoneally, and all mice were sacrificed 48 hours after cisplatin injection to collect serum and kidney tissue. The levels of serum creatinine and blood urea nitrogen were detected. The morphological changes of renal tubules were observed by HE staining. Cell death was observed and assessed by TUNEL fluorescence staining. The mitochondrial morphology was observed under electron microscope. Western blot was used to detect the expression level of glutathione peroxidase 4 (GPX4) in tissues, and the expression of 4-hydroxynonenal (4HNE) in renal cortex was observed by immunohistochemistry.

Results

Compared with the normal control group, the levels of serum creatinine and blood urea nitrogen were significantly increased in the cisplatin + DMSO group and cisplatin + propylene glycol group. At the same time, tubular damage and cell death were observed in the mouse tissues, the mitochondria volume was smaller and mitochondrial mites decrease or disappear, GPX4 expression decreases, and 4HNE expression increases in these two groups. Compared with the respective vehicle groups, the levels of serum creatinine and blood urea nitrogen were significantly lower in the cisplatin + Fer-1 group and the cisplatin + paricalcitol group, while renal tubular injury, cell death and mitochondrial morphological changes were significant relief, GPX4 expression was increased, and 4HNE expression was decreased.

Conclusion

Ferroptosis is involved in cisplatin-induced AKI. Paricalcitol inhibits ferroptosis by GPX4 to attenuate cisplatin-induced AKI.

Funding

  • Government Support - Non-U.S.