1. Academic Validation
  2. Cuproptosis associated cytoskeletal destruction contributes to podocyte injury in chronic kidney disease

Cuproptosis associated cytoskeletal destruction contributes to podocyte injury in chronic kidney disease

  • Am J Physiol Cell Physiol. 2024 May 27. doi: 10.1152/ajpcell.00497.2023.
Han Li 1 Yingjie Fu 2 Yue Xu 2 Hongjun Miao 2 Haonan Wang 2 Tongtong Zhang 2 Xuejian Mei 2 Yinglang He 2 Aihua Zhang 3 Xuhua Ge 1
Affiliations

Affiliations

  • 1 Department of Emergency/Critical Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China.
  • 2 Department of Emergency/Critical Medicine, Children's Hospital of Nanjing Medical University, China.
  • 3 Department of Nephrology, Nanjing Children's Hospital, Nanjing, Jiangsu, China.
Abstract

The podocyte Cytoskeleton determines the stability of podocyte structure and function, and their imbalance plays a pathogenic role in podocyte diseases. However, the underlying mechanism of podocyte Cytoskeleton damage is not fully understood. Here, we investigate the specific role of Cuproptosis in inducing podocyte Cytoskeleton injury. In vitro and in vivo studies, exposure to high levels of copper and adriamycin (ADR) caused significant increases in copper concentration in intracellular and renal tissue. Moreover, excessive accumulation of copper induced Cuproptosis, resulting in the destruction of the podocyte Cytoskeleton. However, inhibition of copper accumulation to reduce Cuproptosis also significantly alleviated the damage of podocyte Cytoskeleton. In addition, inhibition of Cuproptosis mitigated ADR-induced mitochondrial damage as well as the production of Reactive Oxygen Species and depolarization of mitochondrial membrane potential, and restored ATP synthesis. Among the transcriptome Sequencing data, the difference of CXCL5 was the most significant. Both high copper and ADR exposure can cause up-regulation of CXCL5, and CXCL5 deletion inhibits the occurrence of Cuproptosis, thereby alleviating the podocyte Cytoskeleton damage. This suggests that CXCL5 may act upstream of Cuproptosis that mediates podocyte Cytoskeleton damage. In conclusion, Cuproptosis induced by excessive copper accumulation may induce podocyte Cytoskeleton damage by promoting mitochondrial dysfunction, thereby causing podocyte injury. This indicates that Cuproptosis plays an important role in the pathogenesis of podocyte injury and provides a basis for seeking potential targets for the treatment of chronic kidney disease.

Keywords

copper accumulation; cuproptosis; mitochondrial dysfunction; podocyte cytoskeleton; podocyte injury.

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