Loss of oxidative stress tolerance in hypertension is linked to reduced catalase activity and increased c-Jun NH2-terminal kinase activation |
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| Affiliation: | 1. Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Brazil;2. Experimental Neurology Division, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Brazil, Brazil;3. Department of Biophisics, Universidade Federal de Minas Gerais, Brazil, Brazil;4. Heart Institute, Department of Hpertension, Universidade de Sao Paulo, Brazil, Brazil;1. Carlota Saldanha Lab, Instituto Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal;2. IINFACTS-CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Penafiel, Portugal;3. Serviço Cardiologia, Hospital Santa Marta, Centro Hospitalar Lisboa Central (CHLC), Lisboa, Portugal;4. Maria Carmo-Fonseca Lab, Instituto Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal;5. Centro de Estudos do Ambiente e do Mar (CESAM) & Departamento de Biologia Animal (DBA), Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal;6. Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Lisboa, Portugal;7. Instituto de Bioengenharia e Biociências (IBB), Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal;1. Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan;2. Department of Oral and Maxillofacial Surgery, Gifu Prefectural General Medical Centre, Gifu, Japan;1. Laboratory of Vascular Biology, Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil;2. Laboratory of Hemodynamics and Cardiovascular Technology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, BM 5128 Station 17, CH-1015 Lausanne, Switzerland |
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| 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 (H2O2) 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 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 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 H2O2-mediated apoptosis. Inhibition of c-Jun NH2-terminal kinase (JNK) with SP600125 partially rescued H2O2-induced apoptosis in WKY 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. |
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