Complement C3 exacerbates renal interstitial fibrosis by facilitating the M1 macrophage phenotype in a mouse model of unilateral ureteral obstruction.
The impact of the renal microenvironment on macrophage phenotype determination can contribute to the progression or resolution of renal fibrosis. Although the complement proteins affect macrophage polarization, whether complement component 3 (C3) can induce macrophage polarization and regulate renal interstitial fibrosis remains undetermined. In the present study, we investigated the contribution of C3 on macrophage polarization and renal fibrosis in C3-deficient mice with unilateral ureteral obstruction and bone marrow-derived macrophages. C3-deficient mice exhibited attenuated renal fibrosis and ameliorated peritubular capillary rarefaction. Lack of C3 contributed to M2 macrophage polarization, increased IL-10 and VEGF164, and decreased TNF-α and soluble VEGF receptor 1 expression in the obstructed kidneys at the early stages of unilateral ureteral obstruction. C3a facilitated LPS-induced M1 polarization and inflammatory factor production in bone marrow-derived macrophages in vitro, accompanied by increased ERK, NF-κB, and STAT1 phosphorylation. The ERK-specific inhibitor PD98059 inhibited the phosphorylation of ERK, NF-κB, and STAT1 and attenuated M1 polarization-related inflammatory factor production. Furthermore, the culture supernatant from M1 macrophages and C3a-treated M2 macrophages were more detrimental to angiogenesis compared with M2 macrophage supernatants. Thus, complement C3 exacerbates renal interstitial fibrosis by facilitating macrophage M1 polarization, promoting proinflammatory cytokine expression, and deteriorating peritubular capillary rarefaction in the kidney.
['Cui|Jiong|J|', 'Wu|Xiaoting|X|', 'Song|Yankun|Y|', 'Chen|Yi|Y|', 'Wan|Jianxin|J|']
D000818:Animals D001854:Bone Marrow Cells D003176:Complement C3 D007668:Kidney D007674:Kidney Diseases D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D014517:Ureteral Obstruction
renal interstitial fibrosis macrophage polarization complement component 3 peritubular capillary density