Department of General Practice, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Transl Res. 2024 Nov;273:1-15. doi: 10.1016/j.trsl.2024.06.004. Epub 2024 Jun 28.
Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852-1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing mA modification. Specifically, IGF2BP3 recognizes mA motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.
肾脏衰老及随后的肾脏相关疾病的增加归因于肾小管上皮细胞（RTEC）的衰老。我们的研究表明，胰岛素样生长因子 2 mRNA 结合蛋白 3（IGF2BP3）的异常表达，一种 RNA N6-甲基腺苷的阅读器，在顺铂诱导的肾小管衰老中起着关键作用。在顺铂诱导的 RTEC 衰老中，IGF2BP3 的启动子活性和转录明显受到抑制。这是由于 MYC 原癌基因（MYC）的下调所致，MYC 通过结合 IGF2BP3 启动子 1852-1863 位的假定位点调节 IGF2BP3 的转录。IGF2BP3 的过表达可改善顺铂诱导的肾小管衰老。机制研究表明，IGF2BP3 通过增强细胞周期蛋白依赖性激酶 6（CDK6）mRNA 稳定性和增加其表达来抑制 RTEC 中的细胞衰老。IGF2BP3 对管状衰老的抑制作用部分被 CDK6 的敲低逆转。此外，IGF2BP3 通过识别 mA 修饰来募集核帽结合蛋白亚单位 1（NCBP1）并抑制 CDK6 mRNA 衰变。具体而言，IGF2BP3 在 CDK6 mRNA 的 5'非翻译区（UTR）区域的核苷酸 110-114 处识别 mA 基序“GGACU”。在顺铂诱导的急性肾损伤（AKI）向慢性肾脏病（CKD）模型中证实了 IGF2BP3/CDK6 对减轻管状衰老的作用。临床数据还表明，在肾组织或来自患者的血清样本中，IGF2BP3 和 CDK6 的水平随年龄的增长而降低。这些发现表明，IGF2BP3/CDK6 可能是顺铂诱导的管状衰老和肾衰竭的有前途的靶点。
