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Loss of CDK12 drives renal lipotoxicity and fibrosis through NCEH1 intronic polyadenylation
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DOI：10.1186/s13059-026-04239-z.png)
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Abstract
En 中文
Cyclin-dependent kinase 12 (CDK12) has been identified as a susceptibility locus for kidney function, but its role in chronic kidney disease (CKD) remains unclear. We generated tubule-specific CDK12 knockdown and overexpression mice and establish CKD models via adenine-induced and unilateral ureteral obstruction. We assessed renal injury, lipid metabolism, and transcriptional alterations using histology, functional assays, full-length transcriptome sequencing, and mechanistic rescue experiments. We detected significant reduction of CDK12 expression in renal tubular epithelial cells in human patients and experimental chronic kidney disease models. We find tubule-specific CDK12 knockdown exacerbates renal dysfunction, fibrosis, and lipid accumulation, whereas CDK12 overexpression confers protection. Mechanistically, CDK12 deficiency induces intronic polyadenylation of NCEH1 (neutral cholesterol ester hydrolase 1), resulting in reduced NCEH1 expression and cholesteryl ester accumulation. Restoring NCEH1 partially rescues lipid dysregulation and renal injury, identifying it as a key downstream effector. This study reveals that CDK12 protects against CKD progression by suppressing NCEH1 intronic polyadenylation and maintaining lipid homeostasis. The CDK12-NCEH1 axis represents a previously unrecognised mechanism linking transcriptional regulation to renal lipotoxicity and fibrosis, and may provide a potential therapeutic target.
Keywords:
Chronic kidney disease
CDK12
Intronic polyadenylation
Cholesterol ester
NCEH1
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