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CDKAL1 dysfunction impairs lysine codon translation in podocytes and accelerates chronic kidney disease
Hiroko Nagata1,2, Yu Nagayoshi1,3, Takeshi Chujo1
1Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
The EMBO Journal
|March 28, 2026
Summary
Cdkal1 dysfunction directly causes chronic kidney disease (CKD) progression in mice, independent of diabetes. This tRNA modification defect impairs kidney function by affecting protein translation in podocytes.
Area of Science:
- Molecular Biology
- Genetics
- Nephrology
Background:
- Genome-wide association studies link CDKAL1 variants to type 2 diabetes mellitus (DM) and chronic kidney disease (CKD).
- The independent role of CDKAL1 in CKD pathogenesis, separate from diabetes, remains unclear.
Purpose of the Study:
- To investigate the direct role of Cdkal1 in kidney function and CKD progression.
- To elucidate the molecular mechanisms by which Cdkal1 dysfunction impacts kidney health.
Main Methods:
- Systemic and podocyte-specific Cdkal1 knockout mouse models were utilized.
- Analysis of kidney function, podocyte biology, tRNA modification, and protein translation was performed.
Main Results:
- Cdkal1 deficiency in mice led to CKD phenotypes, demonstrating its necessity for kidney function.
- Cdkal1 knockout podocytes exhibited impaired lysine-codon translation and reduced levels of essential lysine-rich proteins, affecting cell migration.
- Overexpression of CD2AP partially rescued these podocyte defects.
Conclusions:
- Cdkal1 is crucial for maintaining kidney function and its dysfunction directly drives CKD progression, independent of diabetes.
- Defective tRNA modification (tRNA modopathy) contributes mechanistically to kidney disease progression.
- These findings highlight a novel link between tRNA modification and kidney health.
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