Activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress contributes to lead-induced nephrotoxicity

• Published in: Biochimica et biophysica acta. Molecular cell research 2019-04, Vol.1866 (4), p.713-726
• Main Authors: Wang, Min-Ge, Fan, Rui-Feng, Li, Wen-Hui, Zhang, Dong, Yang, Du-Bao, Wang, Zhen-Yong, Wang, Lin
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Lead; PERK-eIF2α-ATF4-CHOP pathway; Proximal tubular cells
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2018.12.002

Lead (Pb) is a known nephrotoxicant that causes damage to proximal tubular cells. PERK pathway plays an important role in the pathogenesis of renal diseases, but its role in Pb-induced nephrotoxicity remains largely unknown. In this study, data showed that Pb could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eIF2α-ATF4-CHOP axis in primary rat proximal tubular (rPT) cells, indicating the activation of PERK-eIF2α-ATF4-CHOP pathway due to excessive ER stress. Pb-activated PERK pathway can be effectively inhibited by 4-phenylbutyric acid and PERK gene silencing, respectively; whereas continuously up-regulated by tunicamycin (TM) treatment. Moreover, Pb-induced apoptosis and inhibition of autophagic flux in rPT cells were significantly augmented and aggravated by co-treatment with TM, respectively. Pharmacological or genetic inhibition of the PERK pathway results in alleviation of apoptosis and restoration of autophagy inhibition in Pb-exposed rPT cells. Mechanistically, activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress in rPT cells leads to Pb-induced apoptosis and blockage of autophagic flux, resulting in nephrotoxicity. [Display omitted] •Activated PERK pathway due to excessive ER stress is involved in Pb-treated rPT cells.•Pb-activated PERK pathway facilitates apoptosis in rPT cells.•Pb-activated PERK pathway contributes to autophagy inhibition in rPT cells.