Ding Xuebing, Ma Mingming, Teng Junfang, Shao Fengmin, Wu Erxi, Wang Xuejing
Department of Neurology, The First Affiliated Hospital of Zhengzhou, Zhengzhou, 450052, Henan, China.
Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China.
J Cell Biochem. 2016 Jan;117(1):163-71. doi: 10.1002/jcb.25261.
In recent studies, we found that Numb is involved in oxidative stress-induced apoptosis of renal proximal tubular cells; however, its function on ER stress-induced apoptosis in proteinuric kidney disease remains unknown. The objective of the present study is to explore the role of Numb in urinary albumin-induced apoptosis of human renal tubular epithelial cells (HKCs). In this study, we demonstrate that incubation of HKCs with bovine serum albumin (BSA) resulted in caspase three-dependent cell death. Numb expression was down-regulated by BSA in a time- and dose-dependent manner. Knockdown of Numb by siRNA sensitized HKCs to BSA-induced apoptosis, whereas overexpression of Numb protected HKCs from BSA-induced apoptosis. Moreover, BSA activated CHOP/PERK signaling pathway in a time- and dose-dependent manner as indicated by increased expression of CHOP, PERK, and P-PERK. Furthermore, knockdown of CHOP or PERK significantly attenuated the promoting effect of Numb on BSA-induced apoptosis, while overexpression of CHOP impaired the protective effect of Numb on BSA-induced apoptosis. Taken together, our findings demonstrate that Numb plays a protective role on BSA-induced apoptosis through inhibiting CHOP/PERK signaling pathway in human renal tubular epithelial cells. Therefore, the results from this study provides evidence that Numb is a new target of ER-associated apoptotic signaling networks and Numb may serve as a promising therapeutic target for proteinuric diseases.
在最近的研究中，我们发现Numb参与氧化应激诱导的肾近端小管细胞凋亡；然而，其在蛋白尿性肾病内质网应激诱导的细胞凋亡中的作用尚不清楚。本研究的目的是探讨Numb在尿白蛋白诱导的人肾小管上皮细胞（HKCs）凋亡中的作用。在本研究中，我们证明用牛血清白蛋白（BSA）孵育HKCs会导致半胱天冬酶3依赖性细胞死亡。Numb表达被BSA以时间和剂量依赖性方式下调。用小干扰RNA敲低Numb使HKCs对BSA诱导的凋亡敏感，而Numb的过表达保护HKCs免受BSA诱导的凋亡。此外，如CHOP、PERK和磷酸化PERK表达增加所示，BSA以时间和剂量依赖性方式激活CHOP/PERK信号通路。此外，敲低CHOP或PERK显著减弱Numb对BSA诱导凋亡的促进作用，而CHOP的过表达削弱Numb对BSA诱导凋亡的保护作用。综上所述，我们的研究结果表明，Numb通过抑制人肾小管上皮细胞中的CHOP/PERK信号通路对BSA诱导的凋亡起保护作用。因此，本研究结果提供了证据表明Numb是内质网相关凋亡信号网络的一个新靶点，并且Numb可能作为蛋白尿性疾病的一个有前景的治疗靶点。
