期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1866, 期 4, 页码 713-726出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2018.12.002
关键词
Lead; PERK-eIF2 alpha-ATF4-CHOP pathway; Autophagy; Apoptosis; Proximal tubular cells
资金
- National Natural Science Foundation of China [31873030]
- Shandong Province Natural Science Foundation Doctor Branch [ZR2018BC048]
- Funds of Shandong Double Tops Program
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 eIF2 alpha-ATF4-CHOP axis in primary rat proximal tubular (rPT) cells, indicating the activation of PERK-eIF2 alpha-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-eIF2 alpha-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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