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Kidney Week

Abstract: SU-OR02

Cyclin G1/CDK5-Mediated Dedifferentiation of Proximal Tubular Cells Drives AKI-to-CKD Transition

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Taguchi, Kensei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Elias, Bertha C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Acute kidney injury (AKI) is associated with increased morbidity and mortality in hospitalized patients and predisposes patients to chronic kidney disease (CKD). While kidney cells, particularly proximal tubule cells (PTCs), can undergo dedifferentiation, proliferation, and re-differentiation to facilitate kidney repair after injury, maladaptive repair resulting in prolonged dedifferentiation of PTCs drives fibrosis. We have found that cyclin G1 (CG1), an atypical cyclin, not only promotes G2/M cell cycle arrest, but also regulates dedifferentiation of PTCs. The aim of the current study is to determine if CG1 regulates dedifferentiation through its cyclin dependent kinase, CDK5.


1; Aristolochic acid nephropathy (AAN) was induced by administration of three doses of AA in 8 to 12-week-old male wild-type (WT) and CG1 globally knockout mice (CG1KO). 2; Unilateral ureteral obstruction (UUO) was performed and kidneys were harvested on day 9. 3; To determine the interacting partners of CG1, immunoprecipitation (IP) was performed in CG1-overexpressing LLC-PK1 cells treated with AA. 4; To examine the pathological role of CDK5, LLC-PK1 cells or primary PTCs with or without siRNA or pharmacological inhibitors of CDK5 were treated with AA.


CG1 was rapidly upregulated in PTCs in response to kidney injury and remained high in chronic phase following AAN and UUO. Kidney fibrosis and markers of dedifferentiation, such as SOX9, Vimentin, and Snail, were reduced in CG1KO animals following AAN and UUO injuries, compared to WT. IP demonstrated that CG1 binds to p53, mouse double minute 2 homolog (MDM2), and CDK5. Of these, the interaction of CG1 activates CDK5 and translocates the complex into nuclei. Phosphorylation of CDK5 in response to injury was reduced by genetic ablation of CG1. Genetic or pharmacological inhibition of CDK5 preserved E-cadherin in AA-induced cellular injury with reduction of profibrotic markers; however, it showed no additional effect in CG1KO PTCs.


CG1 partnering with CDK5 drives a maladaptive dedifferentiation of PTCs after kidney injury, resulting in increased secretion of profibrotic cytokines and progression of fibrosis. As CG1 is highly expressed in injured PTCs, it represents a potential therapeutic target for prevention of kidney fibrosis.


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