Children’s Nutrition Research Center Staff Publications
Language
English
Publication Date
9-5-2024
Journal
Communications Biology
DOI
10.1038/s42003-024-06792-4
PMID
39237614
PMCID
PMC11377573
PubMedCentral® Posted Date
9-5-2024
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Cisplatin, Animals, Acute Kidney Injury, eIF-2 Kinase, Endoplasmic Reticulum Stress, Mice, Male, Apoptosis, Mice, Inbred C57BL, Antineoplastic Agents, Phosphorylation
Published Open-Access
yes
Recommended Citation
Yang, Yuxue; Xiong, Ting; Wang, Ti; et al., "Small Gtp-Binding Protein GDP Dissociation Stimulator Influences Cisplatin-Induced Acute Kidney Injury via Perk-Dependent Er Stress" (2024). Children’s Nutrition Research Center Staff Publications. 307.
https://digitalcommons.library.tmc.edu/staff_pub/307
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