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Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E.

Authors
  • Liu, Lele1
  • Deng, Yuanjun1
  • Cai, Yang1
  • Lu, Pingfan1
  • Guo, Yiyan1
  • Zhang, Chunjiang1
  • Li, Qian1
  • Zhang, Tianjing1
  • Han, Min1
  • Xu, Gang1
  • 1 Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. , (China)
Type
Published Article
Journal
AJP Renal Physiology
Publisher
American Physiological Society
Publication Date
Mar 01, 2020
Volume
318
Issue
3
Identifiers
DOI: 10.1152/ajprenal.00367.2019
PMID: 32036696
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKO mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.

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