Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation
Yi-Lin Zhang1, Tao-Tao Tang1, Wei-Jie Ni1
1Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
Abstract:
Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.
Insights
Cyclin-dependent kinase 12 (CDK12) downregulation in kidney cells worsens acute kidney injury (AKI) by impairing DNA repair. Restoring CDK12 levels may prevent drug-induced kidney damage.
Area of Science:
- Nephrology
- Molecular Biology
- Oncology
Background:
- Medications, particularly chemotherapy, can cause direct tubular injury leading to acute kidney injury (AKI).
- Cyclin-dependent kinase 12 (CDK12) inhibition causes transcriptional defects, DNA repair deficiencies, and genomic instability in cancer.
- AKI occurs in 10-25% of patients treated with CDK12 inhibitors, with mechanisms poorly understood.
Purpose of the Study:
- To investigate the role of CDK12 in the development of AKI.
- To elucidate the underlying molecular mechanisms by which CDK12 affects renal tubular cells.
- To assess the therapeutic potential of modulating CDK12 for AKI prevention.
Main Methods:
- Examined CDK12 expression in renal tubular epithelial cells from AKI patients and murine AKI models.
- Utilized tubular cell-specific CDK12 knockdown and overexpression in mice to assess AKI susceptibility.
- Employed single molecule real-time (SMRT) sequencing on kidneys from CDK12RTEC+/- mice to identify targeted genes.
Main Results:
- CDK12 was found to be downregulated in renal tubular epithelial cells in both human AKI cases and mouse models.
- Knockdown of CDK12 in mouse kidneys exacerbated cisplatin-induced AKI, increasing genome instability, apoptosis, and inhibiting proliferation.
- CDK12 knockdown led to transcriptional elongation defects in Fgf1 and Cast genes, enhancing genome instability and apoptosis.
Conclusions:
- Downregulation of CDK12 potentiates AKI development by causing transcriptional elongation defects in key genes like Fgf1 and Cast.
- CDK12 plays a protective role in the kidney against drug-induced injury.
- Increased attention should be directed towards patients receiving CDK12 inhibitors to proactively prevent AKI.
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