Deficiency of C3a receptor attenuates the development of diabetic nephropathy
Objective Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-05-01
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| Series: | BMJ Open Diabetes Research & Care |
| Online Access: | https://drc.bmj.com/content/7/1/e000817.full |
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| author | Ming-hui Zhao Xiao-Qian Li Dong-Yuan Chang |
| author_facet | Ming-hui Zhao Xiao-Qian Li Dong-Yuan Chang |
| author_sort | Ming-hui Zhao |
| collection | DOAJ |
| description | Objective Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN.Research design and methods The expression of C3aR was examined in the renal specimen of patients with DN. Using a C3aR gene knockout mice (C3aR−/−), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a.Results Compared with normal controls, the renal expression of C3aR was significantly increased in patients with DN. C3aR−/− diabetic mice developed less severe diabetic renal damage compared with wild-type (WT) diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T-cell adaptive immunity in C3aR−/− diabetic mice compared with WT diabetic mice, and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophage infiltration. In vitro study demonstrated C3a can enhance macrophage-secreted cytokines which could induce inflammatory responses and differentiation of T-cell lineage.Conclusions C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T-cell adaptive immunity, possibly by influencing macrophage-secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN. |
| format | Article |
| id | doaj-art-134ee5f1c5494c6bb1d1deefc4d328c8 |
| institution | OA Journals |
| issn | 2052-4897 |
| language | English |
| publishDate | 2019-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Diabetes Research & Care |
| spelling | doaj-art-134ee5f1c5494c6bb1d1deefc4d328c82025-08-20T02:35:40ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972019-05-017110.1136/bmjdrc-2019-000817Deficiency of C3a receptor attenuates the development of diabetic nephropathyMing-hui Zhao0Xiao-Qian Li1Dong-Yuan Chang2Renal Division, Peking University First Hospital, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, ChinaObjective Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN.Research design and methods The expression of C3aR was examined in the renal specimen of patients with DN. Using a C3aR gene knockout mice (C3aR−/−), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a.Results Compared with normal controls, the renal expression of C3aR was significantly increased in patients with DN. C3aR−/− diabetic mice developed less severe diabetic renal damage compared with wild-type (WT) diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T-cell adaptive immunity in C3aR−/− diabetic mice compared with WT diabetic mice, and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophage infiltration. In vitro study demonstrated C3a can enhance macrophage-secreted cytokines which could induce inflammatory responses and differentiation of T-cell lineage.Conclusions C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T-cell adaptive immunity, possibly by influencing macrophage-secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.https://drc.bmj.com/content/7/1/e000817.full |
| spellingShingle | Ming-hui Zhao Xiao-Qian Li Dong-Yuan Chang Deficiency of C3a receptor attenuates the development of diabetic nephropathy BMJ Open Diabetes Research & Care |
| title | Deficiency of C3a receptor attenuates the development of diabetic nephropathy |
| title_full | Deficiency of C3a receptor attenuates the development of diabetic nephropathy |
| title_fullStr | Deficiency of C3a receptor attenuates the development of diabetic nephropathy |
| title_full_unstemmed | Deficiency of C3a receptor attenuates the development of diabetic nephropathy |
| title_short | Deficiency of C3a receptor attenuates the development of diabetic nephropathy |
| title_sort | deficiency of c3a receptor attenuates the development of diabetic nephropathy |
| url | https://drc.bmj.com/content/7/1/e000817.full |
| work_keys_str_mv | AT minghuizhao deficiencyofc3areceptorattenuatesthedevelopmentofdiabeticnephropathy AT xiaoqianli deficiencyofc3areceptorattenuatesthedevelopmentofdiabeticnephropathy AT dongyuanchang deficiencyofc3areceptorattenuatesthedevelopmentofdiabeticnephropathy |