Tubular-specific CDK12 knockout causes a defect in urine concentration due to premature cleavage of the slc12a1 gene.
Tubular-specific CDK12 knockout causes a defect in urine concentration due to premature cleavage of the slc12a1 gene.
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由于 slc12a1 基因过早裂解，肾小管特异性 CDK12 敲除导致尿液浓度缺陷
DOI：
10.1016/j.ymthe.2022.05.012
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发表时间：
2022-10-05
影响因子：
12.4
通讯作者：
Liu, Bi-Cheng
中科院分区：
文献类型：
--
作者：
Wang, Bin;Wang, Yao;Wen, Yi;Zhang, Yi-Lin;Ni, Wei-Jie;Tang, Tao -Tao;Cao, Jing-Yuan;Yin, Qing;Jiang, Wei;Yin, Di;Li, Zuo-Lin;Lv, Lin -Li;Liu, Bi-Cheng
细胞周期蛋白依赖性激酶12（CDK 12）在基因转录调控中起着重要作用。CDK 12抑制是一种潜在的抗癌治疗策略。然而，一些临床试验表明，CDK抑制剂可能会导致肾功能障碍和电解质紊乱。CDK 12在肾小管上皮细胞（RTECs）中含量丰富，但CDK 12在肾脏生理学中的确切作用仍不清楚。小鼠RTEC中CDK 12的基因敲除导致多饮、多尿和肾积水。这种表型是由于肾脏中Na-K-2Cl协同转运蛋白2（NKCC 2）水平降低导致水重吸收缺陷所致。此外，CKD 12敲除导致Slc 12 a1（其编码NKCC 2）内含子聚腺苷酸化事件增加，这导致Slc 12 a1截短的转录物产生和NKCC 2下调。这些发现为CDK 12通过调节NKCC 2转录维持肾脏稳态提供了新的见解，这解释了在应用CDK 12抑制剂治疗癌症期间发生的关键水和电解质紊乱。因此，这些新型抗癌药物的临床使用存在安全性问题。肾小管上皮细胞特异性CDK 12基因敲除小鼠由于肾脏浓缩缺陷而表现出多饮和多尿。多尿的机制是CKD 12敲除导致Slc 12 a1（其编码NKCC 2）内含子多聚腺苷酸化事件增加，导致Slc 12 a1截短的转录物产生和NKCC 2下调。
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. 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.
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影响因子：
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