Journal
KIDNEY INTERNATIONAL
Volume 65, Issue 4, Pages 1231-1239Publisher
BLACKWELL PUBLISHING INC
DOI: 10.1111/j.1523-1755.2004.00500.x
Keywords
oxidant injury; renal; ERK; JNK; survival
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Funding
- NIDDK NIH HHS [DK-58324-01 A1] Funding Source: Medline
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Background. Our previous studies suggest that the balance between the activation of extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal/stress-activated protein kinase (JNK) might determine cell fate following oxidant injury in vivo. Methods. The mouse proximal tubule cell line (TKPTS) was used to study hydrogen peroxide (H2O2)-induced death and survival. The role of ERK and JNK in this process was studied by using adenoviruses that contain either a constitutively active mitogen-activated protein kinase kinase 1 (MEK1) or a dominant-negative JNK. Acridine orange plus ethidium bromide staining was applied to distinguish between viable, apoptotic, and necrotic cells following H2O2 treatment. We analyzed cell cycle events by fluorescence-activated cell sorter (FACS) analysis and the phosphorylation status of ERK and JNK by Western blotting. Results. TKPTS cells survived a moderate level of oxidative stress (0.5 mmol/L H2O2) via temporary growth arrest, while high dose of H2O2 (1 mmol/L) caused extensive necrosis. Survival was associated with activation of both ERK and JNK, while death was associated with JNK activation only. Prior adenovirus-mediated up-regulation of ERK or inhibition of JNK function increased the survival (8- or 7-fold, respectively) of TKPTS cells after 1 mmol/L H2O2 treatment. Interestingly, ERK activation and, thus, survival was associated with growth arrest not proliferation. Conclusion. We demonstrate that oxidant injury-induced necrosis could be ameliorated by either up-regulation of endogenous ERK or by inhibition of JNK-related pathways. These results directly demonstrate that the intracellular balance between prosurvival and prodeath mitogen-activated protein kinases (MAPKs) determine proximal tubule cell survival from oxidant injury and reveal possible mediators of survival.
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