Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis
Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis
复制标题
DOI：
10.1038/s41598-019-40795-0
复制
发表时间：
2019-03
影响因子：
4.6
通讯作者：
Turgay Saritas;Catherina A. Cuevas;Mohammed Z. Ferdaus;C. Kuppe;R. Kramann;M. Moeller;J. Floege;J. Singer;J. McCormick
中科院分区：
文献类型：
--
作者：
Turgay Saritas;Catherina A. Cuevas;Mohammed Z. Ferdaus;C. Kuppe;R. Kramann;M. Moeller;J. Floege;J. Singer;J. McCormick
Cullin 3 (CUL3) 是泛素蛋白酶体系统的一部分，控制着对正常器官功能至关重要的多个细胞过程，包括细胞周期和 Keap1/Nrf2 信号传导。肾小管特异性 Cul3 破坏会导致肾小管间质纤维化，但对其机制知之甚少。因此，我们测试了这样的假设：细胞周期和 Keap1/Nrf2 通路的失调在 Cul3 破坏时引发肾损伤中发挥作用。Cul3 缺失增加了细胞周期蛋白 E 和 p21 的表达，与不受控制的增殖、DNA 损伤和细胞凋亡相关，所有这些都发生在近曲小管损伤之前。 cdk2-cyclin E抑制剂roscovitine并没有阻止Cul3缺失的影响，反而加剧了肾损伤。尽管 CUL3 底物 Keap1/Nrf2 积累和激活（被认为对肾损伤具有保护作用），但还是发生了损伤。Cul3 破坏导致进行性间质炎症、功能相关的肾纤维化和死亡。最后，我们在几种 AKI 和 CKD 小鼠模型以及纤维化的人肾组织中观察到 CUL3 表达降低。这些数据将 CUL3 基因敲除小鼠确立为一种新型遗传 CKD 模型，其中细胞周期失调可能在引发肾小管损伤中起主要作用，并且 CUL3 失调可能导致急性和纤维化肾病。
Cullin 3 (CUL3) is part of the ubiquitin proteasomal system and controls several cellular processes critical for normal organ function including the cell cycle, and Keap1/Nrf2 signaling. Kidney tubule-specificCul3disruption causes tubulointerstitial fibrosis, but little is known about the mechanisms. Therefore, we tested the hypothesis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney injury uponCul3disruption.Cul3deletion increased expression of cyclin E and p21, associated with uncontrolled proliferation, DNA damage, and apoptosis, all of which preceded proximal tubule injury. The cdk2-cyclin E inhibitor roscovitine did not prevent the effects ofCul3deletion, but instead exacerbated the kidney injury. Injury occurred despite accumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury.Cul3disruption led to progressive interstitial inflammation, functionally relevant renal fibrosis and death. Finally, we observed reduced CUL3 expression in several AKI and CKD mouse models and in fibrotic human kidney tissue. These data establish CUL3 knockout mice as a novel genetic CKD model in which dysregulation of the cell cycle may play a primary role in initiating tubule injury, and that CUL3 dysregulation could contribute to acute and fibrotic kidney disease.