ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO1005

CDK5 Deletion Prevents Proximal Tubule Cell Maladaptive Dedifferentiation and Kidney Fibrosis

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • 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
Background

Acute kidney injury (AKI) occurs in more than 20% of hospitalized patients. AKI not only increases morbidity and mortality risks in patients, but also dramatically increases the incidence of chronic kidney disease (CKD), involving progressive fibrosis and loss of organ function, in a process termed AKI-to-CKD transition. Maladaptive repair and dedifferentiation of proximal tubular cells is a hallmark of AKI-to-CKD transition. Cyclin-dependent kinase 5 (CDK5) is a kinase first identified in neuronal cells that regulates cell cycle exit in basal conditions, while hyperactivation of CDK5 and promotes dedifferentiation, G2/M arrest, and neuronal pathology. The role of CDK5 in kidney tubular cells is largely unknown.

Methods

CDK5fl/fl mice were breed to Six2-Cre to generate tubule specific CDK5 knockout (CDK5Δtub). Wild-type, CDK5fl/fl, and CDK5Δtub mice aged 8-12 weeks were subjected to unilateral ureter obstruction (UUO) model. Inhibition of CDK5 was performed in wild-type mice and primary cultured proximal tubular cells with/without aristolochic acid and markers of dedifferentiation and fibrosis were compared.

Results

Kidney injury increased total CDK5 and phospho-CDK5 levels in proximal tubule cells, which correlated with increased markers of dedifferentiation and fibrosis. Despite having similar levels of G2/M arrest as CDK5fl/fl controls following UUO, CDK5Δtub mice had reduced renal fibrosis following injury. CDK5Δtub mice had markedly reduced numbers of dedifferentiated tubule cells and decreased expression of profibrotic and dedifferentiation markers, compared to injured CDK5fl/fl mice. Administration of a specific inhibitor of hyperactive CDK5, GLX, to wild-type mice subjected to UUO suppressed dedifferentiation and fibrosis similar to CDK5Δtub mice. Suppression of CDK5 in cultured proximal tubular cells resulted in a decrease in profibrotic cytokine secretion and a reduction in dedifferentiation markers, while overexpression of CDK5 induced dedifferentiation.

Conclusion

CDK5 is a novel regulator of AKI-to-CKD transition. Elevated CDK5 in proximal tubule cells increases cell dedifferentiation and secretion of profibrotic cytokines, resulting in exacerbation of fibrosis. Inhibition of proximal tubular dedifferentiation by targeting CDK5 may be a new therapeutic strategy for AKI-to-CKD transition.

Funding

  • NIDDK Support