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

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ID: 98249
2020
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Abstract
Acute kidney injury (AKI) has a high global morbidity associated with an increased risk of death and chronic kidney disease (CKD). Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of AKI to CKD, but the underlying mechanism of abnormal renal tubular repair remains unclear. In this study, we investigated the role of heterotrimeric G stimulatory protein alpha subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (Gsa) 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). Gsa mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine (Scr) levels and more substantial tubular necrosis than wild-type (WT) mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing BrdU+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase2 (CDK2)/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro using Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited CDK2/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. The loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.
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liu2020ablationamerican Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Liu, Lele;Deng, Yuanjun;Cai, Yang;Lu, Pingfan;Guo, Yiyan;Zhang, Chunjiang;Li, Qian;Zhang, Tianjing;Han, Min;Xu, Gang;
Journal american journal of physiology renal physiology
Year 2020
DOI
10.1152/ajprenal.00367.2019
URL
Keywords
cell proliferation aki cdk2 cyclin e gsa

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