2. Academic Validation
  3. TRPA1 promotes cisplatin-induced acute kidney injury via regulating the endoplasmic reticulum stress-mitochondrial damage

TRPA1 promotes cisplatin-induced acute kidney injury via regulating the endoplasmic reticulum stress-mitochondrial damage

  • J Transl Med. 2023 Oct 5;21(1):695. doi: 10.1186/s12967-023-04351-9.
Fei Deng # 1 2 3,  Heping Zhang # 4,  Wei Zhou # 3,  Shijie Ma 3,  Yuwei Kang 5,  Wei Yang 5,  Liangbin Zhao 6,  Wei Qin 7
Affiliations

Affiliations

  • 1 Department of Nephrology, West China Hospital, Sichuan University, 37 Guoxue Alley, Wuhou District, Chengdu, 610044, China.
  • 2 Department of Nephrology, Sichuan Provincial People's Hospital Jinniu Hospital, Chengdu Jinniu District People's Hospital, Chengdu, China.
  • 3 Department of Nephrology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 4 Department of Nephrology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
  • 5 Department of Nephrology, Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 6 Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, 39 Shierqiao Road, Jinniu District, Chengdu, 610072, China. [email protected].
  • 7 Department of Nephrology, West China Hospital, Sichuan University, 37 Guoxue Alley, Wuhou District, Chengdu, 610044, China. [email protected].
  • # Contributed equally.
PMID: 37798747 DOI: 10.1186/s12967-023-04351-9
Abstract

Background: Cisplatin is a widely used and effective chemotherapeutic agent against Cancer. However, nephrotoxicity is one of the most common side effects of cisplatin, and it can proceed to acute kidney injury (AKI). Studies have reported that activation of transient receptor potential ankyrin-1 (TRPA1) mediates cisplatin-induced renal tubular cytotoxic injury. The aim of this study was to investigate the mechanism of TRPA1 in promoting cisplatin-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage.

Methods: A cisplatin-induced HK-2 cell model in vitro and mouse model in vivo were established. The mechanism of TRPA1 promotes AKI was elucidated by H&E staining, TUNEL staining, transmission electron microscope (TEM), immunofluorescence, CCK-8 viability assays, flow cytometry, Western blotting, JC-1 assay, and Enzyme linked immunosorbent assay (ELISA).

Result: In vivo and in vitro, HC-030031 reduced cisplatin-induced Scr and BUN level elevations; improved cisplatin-induced renal tissue injury, Apoptosis, and mitochondrial dysfunction; elevated the reduced ERS-associated proteins glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), and C/EBP homologous protein (CHOP) levels induced by cisplatin; reduced the elevated optic atrophy 1 (OPA1), mito-fusion 1 (MFN1), and mito-fusion 2 (MFN2) protein levels, and elevated phospho-dynamin-related protein 1 (p-DRP1) and mitochondrial fission factor (MFF) protein levels. HC-030031 also reduced the mitochondria-associated endoplasmic reticulum membrane (MAM) structure. In addition, TRPA1 agonists also decreased cell proliferation, increased Apoptosis, and triggered mitochondrial dysfunction and calcium overload in HK-2 cells via modulation of MAM. ERS inhibitors and GRP75 inhibitors reversed these changes caused by TRPA1 agonists.

Conclusion: Our findings suggest that TRPA1 enhances cisplatin-induced AKI via modulation of ERS and mitochondrial damage.

Keywords

Acute kidney injury; Cisplatin; Endoplasmic reticulum stress; Mitochondrial impairment; TRPA1.

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