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

Wang, Bin; Wang, Yao; Wen, Yi; Zhang, Yilin; Ni, Wei-Jie; Tang, Tao-Tao; Cao, Jun; Yin, Qian; Jiang, Wei; Yin, Di; Li, Zuo‐Lin; Lv, Lin‐Li; Liu, Bi‐Cheng

doi:10.1016/j.ymthe.2022.05.012

Cited by 1 publication

(5 citation statements)

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“…To establish the role of tubular CDK12 in the kidney, we first generated TEC-specific CDK12-knockout mice (CDK12 flox/flox , Cdh16-Cre, CDK12 RTEC-/- ) using the Cre-LoxP system and found that CDK12 RTEC-/- mice exhibited severe polyuria and polydipsia with mild renal dysfunction. 18 To better mimic the downregulation of CDK12 expression via using a CDK12 inhibitor, we further generated conditional knockdown mice in which the CDK12 gene was downregulated in TEC by using the Cre-LoxP system. Figure 3 A shows the strategy for generating mice with TEC -specific knockdown of the CDK12 gene.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we found that CDK12 knockout in TECs caused urine concentration defects due to slow Slc12a1 gene transcriptional elongation dynamics and observed that CDK12 regulated DDR in AKI. 18,30 However, it is unclear whether CDK12 knockdown can aggravate kidney injury through transcriptional elongation of genes involved in the DDR. The DDR signaling cascade is pivotal for postinjury repair after AKI.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo virus transduction to overexpress CDK12 was performed as described previously with slight modifications. 18 Briefly, 50 μl of filter-purified lentivirus cocktail (EGFP or EGFP-CDK12, ∼2×10 6 IU/μl) was injected into each kidney. Age and weight-matched C57BL/6 (wild-type) mice were purchased from Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China).…”

Section: Star Methodsmentioning

confidence: 99%

“…Interestingly, we found that CDK12 RTEC-/- mice exhibited severe polyuria and urine retention with renal dysfunction. 18 Such pathologic effects may result from slow transcriptional elongation dynamics of the Slc12a1 gene. 18 These findings suggested an intimate correlation between CDK12 loss and kidney damage.…”

Section: Introductionmentioning

confidence: 99%

“… 18 Such pathologic effects may result from slow transcriptional elongation dynamics of the Slc12a1 gene. 18 These findings suggested an intimate correlation between CDK12 loss and kidney damage. Whether TEC injury and the development of AKI are associated with the extent of CDK12 deficiency needs to be further studied.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang,

Tang,

et al. 2024

Int. J. Biol. Sci.

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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 CDK12 RTEC+/- 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Star Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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