Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Area of Science:

• Nephrology
• Cell Biology
• Molecular Biology

Background:

• Kidney injuries increase renal tubule cell cycle progression, aiding acute repair but with an unknown role in chronic kidney disease (CKD).
• The role of ongoing tubular cell cycle progression in the pathogenesis of chronic kidney disease (CKD) remains unclear.

Purpose of the Study:

• To investigate the role of tubular cell cycle progression in CKD.
• To determine if inhibiting cell cycle progression can ameliorate CKD.

Main Methods:

• Utilized FDA-approved CDK4/6 inhibitor to block G1/S phase cell cycle progression in murine CKD models.
• Performed selective deletion of cyclin D1 to assess its role in CKD.
• Analyzed gene expression quantitative trait loci (eQTLs) for CCND1 and CDKN2B in relation to estimated glomerular filtration rate (eGFR).

Main Results:

• CDK4/6 inhibition improved renal function and reduced tubular injury and fibrosis in two CKD models.
• Selective deletion of cyclin D1 paradoxically worsened tubular injury.
• Reduced CDKN2B expression correlated with lower eGFR, while higher CCND1 levels correlated with higher eGFR.
• CDK4/6 inhibition promoted tubular cell survival via a STAT3/IL-1β pathway, dependent on cell cycle effects.

Conclusions:

• Blocking cell cycle progression with CDK4/6 inhibitors, but not cyclin D1 deletion, protects against chronic kidney injury.
• These findings challenge the paradigm that tubular cell cycle progression is beneficial in CKD.
• Inhibition of CDK4/6 offers a potential therapeutic strategy for CKD.