2. Academic Validation
  3. Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation

Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation

  • Free Radic Biol Med. 2023 Dec 13:S0891-5849(23)01155-3. doi: 10.1016/j.freeradbiomed.2023.12.010.
Lingkun Wang 1,  Yaochen Xie 1,  Boneng Xiao 2,  Xuelin He 3,  Guanghui Ying 4,  Huiyan Zha 1,  Chen Yang 1,  Xuejin Jin 5,  Guilin Li 1,  Li Ping 1,  Jincheng Wang 6,  Qinjie Weng 7
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China.
  • 2 Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3 Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Department of Nephrology, Beilun People's Hospital, Ningbo, 315826, China.
  • 4 Department of Nephrology, Beilun People's Hospital, Ningbo, 315826, China.
  • 5 Department of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China.
  • 6 Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Research Institute of Zhejiang University-Taizhou, Taizhou, 318000, China. Electronic address: wangjincheng@zju.edu.cn.
  • 7 Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Research Institute of Zhejiang University-Taizhou, Taizhou, 318000, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. Electronic address: wengqinjie@zju.edu.cn.
PMID: 38101584 DOI: 10.1016/j.freeradbiomed.2023.12.010
Abstract

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced Apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or two hours after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.

Keywords

Acute kidney injury; Cisplatin; Fatty acid oxidation; Isorhamnetin; PGC-1α.

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