Lipotoxicity in renal proximal tubular cells: relationship between endoplasmic reticulum stress and oxidative stress pathways.
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.
Katsoulieris
Elias
E
Renal Research Group, Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, University of Brighton, UK.
Mabley
Jon G
JG
Samai
Mohamed
M
Sharpe
Martyn A
MA
Green
Irene C
IC
Chatterjee
Prabal K
PK
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
D051742:Transcription Factor CHOP; D019308:Palmitic Acid