Tubular-specific CDK12 knockout causes a defect in urine concentration due to premature cleavage of the slc12a1 gene

Abstract

Cyclin-dependent kinase 12 (CDK12) plays a critical role in regulating gene transcription. CDK12 inhibition is a potential anticancer therapeutic strategy. However, several clinical trials have shown that CDK inhibitors might cause renal dysfunction and electrolyte disorders. CDK12 is abundant in renal tubular epithelial cells (RTECs), but the exact role of CDK12 in renal physiology remains unclear. Genetic knockout of CDK12 in mouse RTECs causes polydipsia, polyuria, and hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced Na-K-2Cl cotransporter 2 (NKCC2) levels in the kidney. In addition, CKD12 knockout causes an increase in Slc12a1 (which encodes NKCC2) intronic polyadenylation events, which results in Slc12a1 truncated transcript production and NKCC2 downregulation. These findings provide novel insight into CDK12 being necessary for maintaining renal homeostasis by regulating NKCC2 transcription, which explains the critical water and electrolyte disturbance that occurs during the application of CDK12 inhibitors for cancer treatment. Therefore, there are safety concerns about the clinical use of these new anticancer drugs.

Graphical abstract

Abstract

Renal-tubular-epithelial-cell-specific CDK12 knockout mice presented with polydipsia and polyuria due to renal concentrating defects. The mechanism of polyuria is that CKD12 knockout causes an increase in Slc12a1 (which encodes NKCC2) intronic polyadenylation events, resulting in Slc12a1 truncated transcript production and NKCC2 downregulation.