title: Loss of oxidative stress tolerance in hypertension is linked to reduced catalase activity and increased c-Jun NH2-terminal kinase activation.
abstract: 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 (H(2)O(2)) is enhanced in immortalized renal proximal tubular epithelial cells from spontaneously hypertensive rats (SHR) compared to normotensive control Wistar Kyoto rats (WKY). We found that SHR cells were more sensitive to H(2)O(2)-induced cell death than WKY cells. Lower survival in SHR cells correlated with increased DNA fragmentation, chromatin condensation, and caspase-3 activity, indicating apoptosis. H(2)O(2) degradation was slower in SHR than in WKY 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 H(2)O(2)-mediated apoptosis. Inhibition of c-Jun NH(2)-terminal kinase (JNK) with SP600125 partially rescued H(2)O(2)-induced apoptosis in WKY but not in SHR cells. In addition, p54 JNK2 isoform was robustly phosphorylated by H(2)O(2), this effect being more pronounced in SHR cells. Together, these results suggest that the survival disadvantage of SHR cells upon exposure to H(2)O(2) stems from impaired antioxidant mechanisms and activated JNK proapoptotic signaling pathways.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. pgomes@med.up.pt
authors.forename: Pedro
authors.initials: P
authors.lastname: Gomes
authors.forename: Sónia
authors.initials: S
authors.lastname: Simão
authors.forename: Vera
authors.initials: V
authors.lastname: Lemos
authors.forename: João S
authors.initials: JS
authors.lastname: Amaral
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013329:Structure-Activity Relationship
chemical_list: D006861:Hydrogen Peroxide; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases