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Kidney Week

Abstract: PO0408

Hyperactivation of CDK5 Promotes Proximal Tubule Cell Dedifferentiation and Interstitial Fibrosis in CKD

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • 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

Chronic kidney disease (CKD) effects ~15% of the world’s population. Recently, we demonstrated that Cyclin G1 (CG1) regulates proximal tubule cells (PTCs) G2/M arrest and promotes fibrosis. CG1 is known to act through Cyclin dependent kinase 5 (CDK5), which regulates cell cycle exit and homeostasis in differentiated cells. Under normal conditions, CDK5 activity is kept in check by p35; however, during cellular stress p35 is cleaved to p25, leading to hyperactivation of CDK5, a leading driver of many neurodegenerative diseases. The aim of the current study is to determine if CG1 induced hyperactivation of CDK5 plays a pathological role in PTCs dedifferentiation and profibrotic signaling.

Methods

A novel CDK5/p25 inhibitor, Glixx, was utilized to inhibit hyperactivation of CDK5. Protocol 1; Aristolochic acid nephropathy (AAN) and low-dose cisplatin model were conducted as AKI-to-CKD model by repeated doses of AA and cisplatin in 8 to 12-week-old male wild-type (WT) and CG1 globally knockout mice (CG1KO). Protocol 2; To investigate the effect of CDK5 hyperactivation, unilateral ureter obstruction (UUO) was conducted with administration of Glixx. Protocol 3; CDK5 was overexpressed in cultured PTCs. Protocol 4; Primary PTCs of WT and CG1KO mice were co-incubated with AA in the presence or absence of Glixx or roscovitine, a selective CDK inhibitor.

Results

AAN and low-dose cisplatin induce phosphorylation and activation of CDK5 in wild-type but not CG1KO kidneys. Expression and cleavage of p35 to p25 is also reduced in CG1KO PTCs compared to wild-type. Inhibition of CDK5 or CDK5/p25 interaction (hyperactivation) prevents dedifferentiation and profibrotic cytokine secretion in AA treated primary PTCs. Overexpression of either CG1 or CDK5 induces upregulation of dedifferentiation and profibrotic markers, which can be reversed through inhibition of CDK5. In vivo, inhibition of CDK5/p25 binding reduces fibrosis and prevents PTC dedifferentiation following UUO.

Conclusion

CG1 expression induces hyperactivation of CDK5 in PTCs. Inhibition of CDK5 or CDK5/p25 binding prevent CG1 induced dedifferentiation, profibrotic cytokine secretion and fibrosis. Targeting the CG1/CDK5 pathway is a potential therapeutic target for inhibiting AKI-to-CKD transition.