Article Text
Abstract
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.
- C3a receptor
- diabetic nephropathy
- inflammation
- microarray
- T cell
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Footnotes
Contributors MC designed the study. D-YC collected the renal biopsies. X-QL carried out the experiments, analyzed the data, made the figures and drafted the paper. MC and M-HZ revised the paper. All authors approved the final version of the manuscript.
Funding This study was supported by the grants from the National Key Research and Development Program (No. 2016YFC1305405), two grants from the National Natural Science Fund (Nos. 81425008 and 81621092), the grant by Peking University Health Science Center (No. BMU2017CJ002), and a grant from the University of Michigan Health System and Peking University Health Sciences Center Joint Institute for Translational and Clinical Research.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The study was approved by the Research Ethics Committee of Peking University First Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.