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Int J Biol Sci 2024; 20(5):1669-1687. doi:10.7150/ijbs.90872 This issue Cite

Research Paper

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects

Yi-Lin Zhang1#, Tao-Tao Tang1#, Wei-Jie Ni1, Zhong-Tang Li2, Liang-Yun-Zi Jiang1, Yao Wang3, Xuan Zhou4, Jing-Yuan Cao5, Qing Yin1, Wei Jiang1, Ya-Jie Zhao6, Wei-Hua Gan6, Ai-Qing Zhang6, Zuo-Lin Li1, Yi Wen1, Lin-Li Lv1, Bi-Cheng Liu1✉, Bin Wang1✉

1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
2. Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China.
3. Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
4. Shanghai OE Biotech Co., Ltd., Shanghai, China.
5. Institute of Nephrology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, Jinagsu, China.
6. Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Address for correspondence: Bin Wang, MD, PhD or Bi-Cheng Liu, MD, PhD, Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China. E-mail address: wangbinheweicom or liub More

Citation:
Zhang YL, Tang TT, Ni WJ, Li ZT, Jiang LYZ, Wang Y, Zhou X, Cao JY, Yin Q, Jiang W, Zhao YJ, Gan WH, Zhang AQ, Li ZL, Wen Y, Lv LL, Liu BC, Wang B. Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. Int J Biol Sci 2024; 20(5):1669-1687. doi:10.7150/ijbs.90872. https://www.ijbs.com/v20p1669.htm
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Abstract

Graphic 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.

Keywords: CDK12, Apoptosis, DNA damage, AKI, Proximal tubule, Transcriptional elongation defect, Fgf1, Cast

Citation styles

APA
Zhang, Y.L., Tang, T.T., Ni, W.J., Li, Z.T., Jiang, L.Y.Z., Wang, Y., Zhou, X., Cao, J.Y., Yin, Q., Jiang, W., Zhao, Y.J., Gan, W.H., Zhang, A.Q., Li, Z.L., Wen, Y., Lv, L.L., Liu, B.C., Wang, B. (2024). Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. International Journal of Biological Sciences, 20(5), 1669-1687. https://doi.org/10.7150/ijbs.90872.

ACS
Zhang, Y.L.; Tang, T.T.; Ni, W.J.; Li, Z.T.; Jiang, L.Y.Z.; Wang, Y.; Zhou, X.; Cao, J.Y.; Yin, Q.; Jiang, W.; Zhao, Y.J.; Gan, W.H.; Zhang, A.Q.; Li, Z.L.; Wen, Y.; Lv, L.L.; Liu, B.C.; Wang, B. Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. Int. J. Biol. Sci. 2024, 20 (5), 1669-1687. DOI: 10.7150/ijbs.90872.

NLM
Zhang YL, Tang TT, Ni WJ, Li ZT, Jiang LYZ, Wang Y, Zhou X, Cao JY, Yin Q, Jiang W, Zhao YJ, Gan WH, Zhang AQ, Li ZL, Wen Y, Lv LL, Liu BC, Wang B. Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. Int J Biol Sci 2024; 20(5):1669-1687. doi:10.7150/ijbs.90872. https://www.ijbs.com/v20p1669.htm

CSE
Zhang YL, Tang TT, Ni WJ, Li ZT, Jiang LYZ, Wang Y, Zhou X, Cao JY, Yin Q, Jiang W, Zhao YJ, Gan WH, Zhang AQ, Li ZL, Wen Y, Lv LL, Liu BC, Wang B. 2024. Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. Int J Biol Sci. 20(5):1669-1687.

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