CaMKII is involved in subcellular Ca2+ redistribution-induced endoplasmic reticulum stress leading to apoptosis in primary cultures of rat proximal tubular cells exposed to lead
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Min-Ge Wang1,2,3, Wen-Hui Li1,2,3, Xin-Yu Wang1,2,3, Du-Bao Yang1,2,3, Zhen-Yong Wang1,2,3 and Lin Wang1,2,3
1College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an City, Shandong Province, 271018, China
2Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an City, Shandong Province, 271018, China
3Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an City, Shandong Province, 271018, China
Lin Wang, email: firstname.lastname@example.org
Keywords: lead, calcium, proximal tubular cells, CaMKII, endoplasmic reticulum stress
Received: June 15, 2017 Accepted: July 25, 2017 Published: August 08, 2017
Lead (Pb) is a known nephrotoxic element. Recently we have proved that subcellular Ca2+ redistribution is involved in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells, but the underlying mechanism remains to be elucidated. Firstly, data showed that Pb triggers endoplasmic reticulum (ER) stress response in rPT cells, as evidenced by the elevations of ER stress markers. Moreover, pharmacological modulation of Ca2+ mobilization in ER and cytoplasm with three chemicals (2-APB or TG or BAPTA-AM) can effectively increase or decrease the protein expression of ER stress markers in Pb-exposed rPT cells, demonstrating that Pb-induced ER stress is Ca2+-dependent. We found that Pb stimulates phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) to activate its activity. Meanwhile, inhibition of CaMKII with KN93 or KN62 attenuated Pb-activated caspase-12 and CCAAT/enhancer-binding protein homologous protein (CHOP) in rPT cells, demonstrating that CaMKII activation promoted ER stress in rPT cells. Likewise, Pb-induced apoptosis can be effectively inhibited by CaMKII inhibitor KN93 or KN62. Furthermore, co-treatment with KN93 or KN62 significantly reversed Pb-induced ER Ca2+ release and concomitant intracellular Ca2+ overload in rPT cells. In summary, these results expound the mechanisms involving in ER stress, Ca2+ dyshomeostasis and activated CaMKII, which all contribute to Pb-induced apoptosis. CaMKII acts as a critical mediator of ER stress and associated apoptosis via regulating intracellular Ca2+ mobilization from ER to cytoplasm.
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