title: Lipotoxicity in renal proximal tubular cells: relationship between endoplasmic reticulum stress and oxidative stress pathways.
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 micromol/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 (H(2)O(2)) combined with SP600125 which blocks c-Jun N-terminal kinase (JNK) activation; salubrinal, which maintains eukaryotic initiation factor 2 alpha 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 H(2)O(2) 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.
authors.affiliation: Renal Research Group, Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, University of Brighton, UK.
authors.forename: Elias
authors.initials: E
authors.lastname: Katsoulieris
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Mohamed
authors.initials: M
authors.lastname: Samai
authors.forename: Martyn A
authors.initials: MA
authors.lastname: Sharpe
authors.forename: Irene C
authors.initials: IC
authors.lastname: Green
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D019308:Palmitic Acid / Q000633:toxicity*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D051742:Transcription Factor CHOP; D019308:Palmitic Acid