2. Academic Validation
  3. Small GTP-binding protein GDP dissociation stimulator influences cisplatin-induced acute kidney injury via PERK-dependent ER stress

Small GTP-binding protein GDP dissociation stimulator influences cisplatin-induced acute kidney injury via PERK-dependent ER stress

  • Commun Biol. 2024 Sep 5;7(1):1091. doi: 10.1038/s42003-024-06792-4.
Yuxue Yang # 1 2,  Ting Xiong # 3,  Ti Wang # 1,  Xiwei Chen 1,  Ziwei Ma 4,  Bangyun Zuo 1,  Dong Ning 5,  Ruilong Song 6,  Xuesong Liu 7,  Daxin Wang 8
Affiliations

Affiliations

  • 1 The Hospital Affiliated to the Medical School of Yangzhou University (Taizhou People's Hospital), No. 366 Taihu Road, Taizhou, Jiangsu, 225300, China.
  • 2 Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
  • 3 Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
  • 4 Clinical Medical College, Dalian Medical University, Dalian, Liaoning, 116044, China.
  • 5 School of Medicine, National University of Ireland Galway, University Road, Galway, 999014, Ireland.
  • 6 College of Veterinary Medicine, Yangzhou University, #88 South University Avenue, Yangzhou, Jiangsu, 225009, China.
  • 7 Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China. seanxsl712@163.com.
  • 8 The Hospital Affiliated to the Medical School of Yangzhou University (Taizhou People's Hospital), No. 366 Taihu Road, Taizhou, Jiangsu, 225300, China. daxinw113@gmail.com.
  • # Contributed equally.
PMID: 39237614 DOI: 10.1038/s42003-024-06792-4
Abstract

Cisplatin is a common Anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA Sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated Apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related Apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and Apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and Apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.

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