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Kidney Week

Abstract: FR-OR28

Cyclin G1 Promotes Proximal Tubule Cell Maladaptive Dedifferentiation and Fibrosis in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


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

Acute Kidney Injury (AKI) frequently occurs in hospitalized patients and predisposes them to developing chronic kidney disease (CKD). This AKI-to-CKD transition promotes irreversible fibrosis, loss of kidney function, and ultimately organ failure. Though the exact molecular mechanisms that are involved in this process are unclear, we and others have shown that maladaptive repair of proximal tubule cells (PTC), G2-M cell cycle arrest, PTC dedifferentiation, upregulation of senescence markers, and secretion of profibrotic cytokines are features of the AKI-to-CKD transition. Here we directly test whether cyclin G1 promotes fibrosis through G2-M arrest of PTCs.


Male BL57Bl/6 (WT) and cyclin G1 knockout (CG1KO) littermates age 8-12 weeks were subjected to 3 different kidney injury models: aristolochic acid nephropathy (AAN), repeat low-dose cisplatin, and unilateral ureter obstruction (UUO) models. Paclitaxel was used to induce G2/M arrest. The expression of cyclin G1, fibrotic markers, and dedifferentiation markers were measured by immunofluorescence, protein expression and/or mRNA levels.


Kidney fibrosis, G2-M arrest and the expression of dedifferentiation markers were all reduced in CG1KO mice when compared to wild-types in all three injury models tested. Treatment with paclitaxel increased G2-M arrest in AAN injured CG1KO mice to similar levels to AAN + paclitaxel treated wild-type mice; however, wild-type mice showed significantly lower kidney function and increased kidney fibrosis compared to CG1KO mice following treatment. While deletion of cyclin G1 did not reduce the number of dedifferentiated cells in the acute phase of injury, the number of dedifferentiated cells in the chronic phase of injury were greatly reduced in all three models tested. Paclitaxel/G2-M arrest did not induce dedifferentiation in CG1KO mice. CG1KO primary PTCs were resistant to AAN and/or paclitaxel induced dedifferentiation and did not develop senescence markers or profibrotic cytokine secretion.


Cyclin G1 regulates G2-M arrest but G2-M arrest in the absence of dedifferentiation does not affect AKI-to-CKD transition. CG1 promotes maladaptive dedifferentiation possibly by activation of CDk5. Inhibition of CG1 and/or CDK5 may be a promising therapeutic strategy to prevent AKI to CKD transition.


  • NIDDK Support