miR-192 Induces G2/M Growth Arrest in Aristolochic Acid Nephropathy
miR-192 Induces G2/M Growth Arrest in Aristolochic Acid Nephropathy
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DOI：
10.1016/j.ajpath.2013.12.028
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发表时间：
2014-04-01
影响因子：
6
通讯作者：
Fraser, Donald J.
中科院分区：
文献类型：
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作者：
Jenkins, Robert H.;Davies, Luke C.;Fraser, Donald J.
马兜铃酸肾病以进展迅速的肾小管间质肾炎为特征，最终发展为终末期肾功能衰竭和尿路上皮恶性肿瘤。马兜铃酸的促纤维化作用与近端肾小管上皮细胞的生长停滞有关；然而，其潜在的机制在很大程度上尚不清楚。MiRNAs是一种小的、内源性的、转录后的基因表达调节因子，参与了许多生理和病理过程。在本研究中，我们研究了马兜铃酸诱导细胞周期停滞的机制以及miRNAs对其的调节作用。与马兜铃酸孵育通过p53介导的成熟促进复合体CDK1/Cyclin-B1的失活，导致近端肾小管上皮细胞G(2)/M显著停滞。MiRNA表达分析表明，miRNAs表达上调，包括miR-192、miR-194、miR-450a和miR-542-3p。MiR-192的稳定过表达概括为通过抑制E3泛素连接酶，小鼠双分钟2，p53的负调控因子，使G(2)/M停滞。P53诱导p21(CiP1)转录、生长停滞和DNA损伤45，并导致成熟促进复合体失活和解离。这些数据表明miR-192在马兜铃酸中毒损伤后介导近端肾小管上皮细胞G(2)/M期停滞中发挥核心作用。由于大量研究已将这种生长抑制与近端肾小管上皮细胞损伤后的纤维化联系起来，这一机制可能与急性肾损伤后的恢复/不恢复具有广泛的相关性。
Aristolochic acid nephropathy is characterized by rapidly progressive tubulointerstitial nephritis culminating in end-stage renal failure and urothelial malignancy. Profibrotic effects of aristolochic acid are linked to growth arrest of proximal tubular epithelial cells; however, the underlying mechanisms are Largely undetermined. miRNAs are small, endogenous, post-transcriptional regulators of gene expression implicated in numerous physiological and pathological processes. In the present study, we characterized the mechanism of aristolochic acid-induced cell cycle arrest and its regulation by miRNAs. Incubation with aristolochic acid led to profound G(2)/M arrest in proximal tubular epithelial cells via p53-mediated inactivation of the maturation-promoting complex, CDK1/cyclin-B1. Analysis of miRNA expression identified up-regulation of miRNAs, including miR-192, miR-194, miR-450a, and miR-542-3p. The stable overexpression of miR-192 recapitulated G(2)/M arrest via repression of the E3 ubiquitin ligase, murine double-minute 2, a negative regulator of p53. p53-induced transcription of p21(ciP1) and growth arrest and DNA damage 45 and resulted in the inactivation and dissociation of the maturation-promoting complex. These data demonstrate a core role for miR-192 in mediating proximal tubular epithelial cell G(2)/M arrest after toxic injury by aristolochic acid. Because numerous studies have linked such growth arrest to fibrosis after proximal tubular epithelial cell injury, this mechanism may have widespread relevance to recovery/nonrecovery after acute kidney injury.