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Kidney Week

Abstract: SA-PO072

Loss of Gsα Impairs Renal Tubular Epithelial Cell Regeneration via the Raf-MEK-ERK Dependent Inhibition of CDK2/Cyclin E Mechanism

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Liu, Lele, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Han, Min, Tongji Hospital, Tongji Medical College, Wuhan, HUBEI, China
  • Xu, Gang, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background

The alpha subunit of the heterotrimeric G stimulatory protein (Gsa), encoded by the guanine nucleotide binding protein, alpha stimulating gene (Gnas), is expressed ubiquitously and mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP) and activation of the protein kinase A signaling pathway. We investigated the roles of Gsa in renal tubular epithelial cell regeneration.

Methods

We generated a distal tubule epithelial-specific Gsa deletion (Gsaflox/flox Ksp-Cre) mouse to demonstrate the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid toxic nephropathy (AAN) and unilateral ischemia reperfusion injury (UIRI). To further explore the effect of Gsa on cell proliferation, we next knocked down Gsa in cultured human HK-2 cells using a specific small interfering RNA.

Results

Gsaflox/flox Ksp-Cre mouse developed more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis after AAN and UIRI. Gsa inactivation dramatically impaired renal tubular epithelial cell regeneration and blocked proliferating tubular cells in G1/S transition due to the reduction in the number of BrdU+ cells and the depression of cyclin-dependent kinase2 (CDK2)/ cyclinE1 activities. In vitro, treatment of renal tubular epithelial cells with Gsa-targeting small interfering RNA inhibited tubular epithelial cells proliferation by preventing cell cycle progression from G1 to S phase. Down-regulation of Gsa inhibited the activity of CDK2/cyclinE1 and inhibited the Raf-MEK-ERK signaling pathway before and after aristolochic acid stimulates HK-2 cells.

Conclusion

Gsa is required for tubular epithelial cell regeneration in the kidney repair stage after AKI. Loss of Gsa could dramatically impair the regeneration of renal tubular epithelial cells by blocking Raf-MEK-ERK pathway.