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Lipotoxicity in renal proximal tubular cells: Relationship between endoplasmic reticulum stress and oxidative stress pathways
Authors:Elias Katsoulieris  Jon G Mabley  Mohamed Samai  Martyn A Sharpe  Irene C Green  Prabal K Chatterjee
Institution:1. Hartford Hospital, Department of Pathology and Laboratory Medicine, Hartford, CT, USA;2. Clinical Laboratory Partners, Newington, CT, USA;1. Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;2. Functional Food Research Center for Well-Being, Chiang Mai University, Chiang Mai, Thailand;1. Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee -247667, Uttarakhand, India;2. Division of Bacteriology and Mycology, Indian Veterinary Research Institute, Izatnagar-, Bareilly -243122, Uttar Pradesh, India;3. College of Pharmacy, Maharishi Markandeshwar University, Mullana- Ambala, 133207, Haryana, India;4. Plant Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee-247667, Uttarakhand, India
Abstract:Hyperlipidemia in the general population has been linked to the development of chronic kidney disease with both oxidative and endoplasmic reticulum stress implicated. Physiological levels (50-300 µmol/L) of saturated fatty acids such as palmitic acid (PA) cause cytotoxicity in vitro. We investigated cell type- and stimulus-specific signaling pathways induced by PA in renal proximal tubular cells and whether oxidative stress leads to ER stress or vice versa and which pathways predominate in signaling for PA-induced apoptosis and necrosis. NRK-52E cells were incubated with PA or hydrogen peroxide (H2O2) combined with SP600125 which blocks c-Jun N-terminal kinase (JNK) activation; salubrinal, which maintains eukaryotic initiation factor 2α in its phosphorylated state and the antioxidant EUK-134 - a superoxide dismutase mimetic with catalase activity. We found that (i) PA causes both oxidative and ER stress leading to apoptosis which is mediated by phosphorylated JNK; (ii) oxidant-induced apoptosis generated by H2O2 involves ER stress signaling and CHOP expression; (iii) the ER stress mediated by PA is largely independent of oxidative stress; (iv) in contrast, the apoptosis produced by PA is mediated partly via oxidative stress. PA-mediated cell signaling in renal NRK-52E cells therefore differs from that identified in neuronal, hepatic and pancreatic beta cells.
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