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  • Title: Activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress contributes to lead-induced nephrotoxicity.
    Author: Wang MG, Fan RF, Li WH, Zhang D, Yang DB, Wang ZY, Wang L.
    Journal: Biochim Biophys Acta Mol Cell Res; 2019 Apr; 1866(4):713-726. PubMed ID: 30528975.
    Abstract:
    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.
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