1. Academic Validation
  2. PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation

PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation

  • Cell Signal. 2023 Nov 13:110969. doi: 10.1016/j.cellsig.2023.110969.
Yuzhen Li 1 Lang Shi 1 Fan Zhao 1 Yanwen Luo 1 Mingjiao Zhang 1 Xiongfei Wu 2 Jiefu Zhu 3
Affiliations

Affiliations

  • 1 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
  • 2 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. Electronic address: rm003155@whu.edu.cn.
  • 3 Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China. Electronic address: jiefuzhu@whu.edu.cn.
Abstract

Cisplatin, an effective anti-cancer drug, always causes acute kidney injury (AKI) by inducing mitochondrial damage. PIM1 is a serine/threonine kinase, which has been shown to regulate mitochondrial function. However, the role and mechanisms of PIM1 in cisplatin-induced AKI remain unexplored. This study aimed to investigate the effects of PIM1 in cisplatin-induced AKI and its underlying mechanisms. To established Cisplatin-induced AKI model, mice were given a single intraperitoneal injection(20 mg/kg) and BUMPT cells were treated with cisplatin(20 μM/L). PIM1 Inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. Drp1 inhibitor P110 and pcDNA3-Drp1K38A were used to inhibit the activation of Drp1 and mitochondrial fission. The Indicators of renal function, renal morphology, Apoptosis and mitochondrial dysfunction were assessed to evaluate cisplatin-induced nephrotoxicity. We observed that PIM1 was activated in cisplatin-induced AKI in vivo and cisplatin-induced tubular cells injury in vitro. PIM1 inhibition aggravated cisplatin-induced AKI in vivo, while PIM1 overexpression attenuated cisplatin-induced kidney injury in vivo and in vitro. Moreover, inhibiting PIM1 exacerbated mitochondrial damage in mice, but overexpressing PIM1 relieved mitochondrial damage in mice and BUMPT cells. In mice and BUMPT cells, inhibiting PIM1 deregulated the expression of p-Drp1S637, overexpressing PIM1 upregulated the ex-pression of p-Drp1S637. And inhibiting Drp1 activity alleviated cell damage in BUMPT cells with PIM1 knockdown or inhibition. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI.

Keywords

Acute kidney injury; Cisplatin; Drp1; Mitochondrial damage; PIM1.

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