Kallikrein-kinin system and oxidative stress in cisplatin-induced ovarian toxicity |
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| Affiliation: | 1. Department of Biophysics, Federal University of São Paulo, 04039-032 São Paulo, SP, Brazil;2. Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900 São Paulo, SP, Brazil;3. School of Arts, Sciences and Humanities, University of Sao Paulo, 03828-000 São Paulo, SP, Brazil;4. Department of Medical Clinic, University of São Paulo, 05403-000 São Paulo, SP, Brazil;5. Department of Immunology, Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil;1. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States;2. Department of Oncology and Hematology, Istituto Superiore di Sanità, Rome, Italy;3. Food and Drug Administration, Division of Drug Safety Research, Silver Spring, United States;4. Brigham and Women’s Hospital, Boston, MA, United States;5. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States;6. Department of Pediatrics, Wayne State University School of Medicine, Children''s Hospital of Michigan, Detroit, MI, United States;7. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States |
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| Abstract: | Kallikrein-kinin system (KKS) is involved in vascular reactivity and inflammatory response to cytotoxic drugs. Since cisplatin is a widely used chemotherapy and its cytotoxic mechanism can trigger inflammation and oxidative damage, in this work we evaluated the role of KKS in an animal model of cisplatin-induced ovarian toxicity. Biomarkers of ovarian stem cells, activity of KKS, inflammation and oxidative damage were measured in ovarian tissue of C57BL/6 female mice treated with vehicle or cisplatin (2.5 mg/kg). Cisplatin group presented greater number of atretic follicles, and lower numbers of antral and total viable follicles. Ki67, DDX4 and OCT-4 markers were similar between groups. Cisplatin triggered plasma and ovarian tissue kallikrein generation; and increased expression of bradykinin receptors B1 and B2. Neutrophil and macrophage infiltration markers increased. Superoxide anion generation also increased, while reduced glutathione levels decreased. These results suggest that KKS is activated and contributes to ovarian injury during cisplatin treatment. |
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| Keywords: | Cisplatin Chemotherapy Inflammatory cytokines Ovarian toxicity Bradykinin |
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