Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 56, Issue -, Pages 112-122Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.11.017
Keywords
Reactive oxygen species; Apoptosis; JNK; Antioxidant enzymes; Kidney; Hypertension; Free radicals
Funding
- Fundacao para a Ciencia e a Tecnologia
- POCI
- FEDER
- Programa Comunitario de Apoio [PIC/IC/83204/2007]
- Fundação para a Ciência e a Tecnologia [PIC/IC/83204/2007] Funding Source: FCT
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Hypertension is accompanied by increased levels of reactive oxygen species, which may contribute to progressive renal injury and dysfunction. Here we tested the hypothesis that sensitivity to exogenous hydrogen peroxide (H2O2) is enhanced in immortalized renal proximal tubular epithelial cells from spontaneously hypertensive rats (SHR) compared to normotensive control Wistar Kyoto rats (WRY). We found that SHR cells were more sensitive to H2O2-induced cell death than WKY cells. Lower survival in SHR cells correlated with increased DNA fragmentation, chromatin condensation, and caspase-3 activity, indicating apoptosis. H2O2 degradation was slower in SHR than in WRY cells, suggesting that reduced antioxidant enzyme activity might be the basis for their increased sensitivity. In fact, catalase activity was downregulated in SHR cells, whereas glutathione peroxidase activity was similar in both cell types. We next examined whether MAPK signaling pathways contributed to H2O2-mediated apoptosis. Inhibition of c-Jun NH2-terminal kinase (JNK) with SP600125 partially rescued H2O2-induced apoptosis in WRY but not in SHR cells. In addition, p54 JNK2 isoform was robustly phosphorylated by H2O2, this effect being more pronounced in SHR cells. Together, these results suggest that the survival disadvantage of SHR cells upon exposure to H2O2 stems from impaired antioxidant mechanisms and activated JNK proapoptotic signaling pathways. (C) 2012 Elsevier Inc. All rights reserved.
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