2. Academic Validation
  3. Both carvedilol and cimetidine alleviate cisplatin-induced nephrotoxicity via downregulating OCT2

Both carvedilol and cimetidine alleviate cisplatin-induced nephrotoxicity via downregulating OCT2

  • Biochim Biophys Acta Mol Basis Dis. 2025 Mar 6;1871(5):167754. doi: 10.1016/j.bbadis.2025.167754.
Huan Wu 1,  Yichun Ning 2,  Zhaoxing Sun 1,  Ji Ji 1,  Min Lu 1,  Xiaoyan Jiao 2,  Xiaoliang Xu 3,  Xiaoqiang Ding 2,  Xin Cheng 4,  Xiaofang Yu 5
Affiliations

Affiliations

  • 1 Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
  • 2 Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Medical Center for Kidney, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
  • 3 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 4 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: xcheng@sibcb.ac.cn.
  • 5 Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Medical Center for Kidney, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China. Electronic address: yu.xiaofang@zs-hospital.sh.cn.
PMID: 40044066 DOI: 10.1016/j.bbadis.2025.167754
Abstract

Background: Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2.

Methods: The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and Apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin.

Results: Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced Apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells.

Conclusion: Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.

Keywords

Carvedilol; Cimetidine; Cisplatin-induced acute kidney injury (Cis-AKI); Drug screening; Kidney organoids; The organic cation transporter 2 (OCT2).

Figures
Products