The protective effect of neutralizing high-mobility group box1 against chronic cyclosporine nephrotoxicity in mice |
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| Affiliation: | 1. Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, Otwock, Poland;2. Department of Hematology, Jagiellonian University, Kraków, Poland;3. Department of Propedeutic Oncology, Medical University of Gdansk & Gdynia Oncology Center, Gdynia, Poland;4. Department of Oncocardiology, Holycross Cancer Center, Kielce, Poland;5. Nicolaus Copernicus University in Toruń, Poland;6. Clinical Oncology Department, Oncology Center in Bydgoszcz, Poland;7. Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, Poznań, Poland;8. Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland;9. Hematology Department, Independent Public Health Care Ministry of the Interior of Warmia and Mazury Oncology Center, Olsztyn, Poland;10. University of Warmia and Mazury, Olsztyn, Poland;11. Internal Medicine and Oncology Clinic, Silesian Medical University, Katowice, Poland;12. Departament of Hematooncology, Markiewicz Memorial Oncology Center, Brzozów, Poland;13. Hematooncology and Bone Marrow Transplantation Clinic, Lublin, Poland;14. St. John''s Cancer Center, Lublin, Poland;15. Department of Clinical Oncology, Regional Specialized Hospital No. 3, Rybnik, Poland;1. Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Hungary;2. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Hungary;3. CycloLab Cyclodextrin Research & Development Laboratory, Ltd., Hungary;1. Bachelor of Health Science, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 811–8582, Japan;2. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 811–8582, Japan;3. Bachelor of Medicine, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 811–8582, Japan;4. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 811–8582, Japan;1. Blood Transfusion Research Institute, Wuxi Red Cross Blood Center, Wuxi, Jiangsu 214021, PR China;2. Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215007, PR China;3. Miami University, Oxford, OH 45056, United States |
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| Abstract: | Background: High-mobility group box1 (HMGB1) is known to be involved in innate immune response through interaction with receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), besides its proper role within the nucleus. Immunological pathways, including TLR signaling, are also involved in chronic cyclosporine (CsA) nephrotoxicity. This study was designed to determine whether neutralizing HMGB1 prevents chronic CsA nephrotoxicity.Methods: Chronic CsA nephrotoxicity was induced by CsA subcutaneous injection daily for 4 weeks under salt-depletion in mice. Anti-HMGB1 neutralizing antibody for HMGB1 blockade (600 mcg/mouse) was administered weekly to mice in the anti-HMGB1 treatment group. The effects of HMGB1 neutralization were evaluated in terms of renal function as well as histological and immunopathological examination.Results: Anti-HMGB1 administration prevented the increases in serum creatinine and 24 h albuminuria and the decrease in creatinine clearance associated with CsA treatment. Increased tubulointerstitial fibrosis and transforming growth factor (TGF)-β immunohistochemical staining associated with CsA treatment were also prevented by anti-HMGB1 administration. Anti-HMGB1 administration prevented the activation of the TLR4 signaling pathway, which resulted in the reduction of nuclear factor kappa B (NF-κB) expression. In cultured tubular cells, anti-HMGB1 pretreatment also prevented the increases in fibronectin and collagen IV levels associated with CsA treatment.Conclusions: Neutralizing HMGB1 with an anti-HMGB1 antibody ameliorated chronic CsA nephrotoxicity via inhibition of the TLR4 signaling pathway. Our study suggests that HMGB1 blockade can be beneficial for increasing allograft survival in renal transplant recipients by protecting against calcineurin inhibitor-induced nephrotoxicity. |
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