Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. In addition to its role in activating the AP, CFB has been implicated in pathological ocular neovascularization, a common feature of several blinding eye diseases, however, with somewhat conflicting results. The focus of this study was to investigate the direct impact of CFB on ocular neovascularization in a tightly controlled environment. Using mouse models of laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), our study demonstrated an increase in CFB expression during pathological angiogenesis. Results from several in vitro and ex vivo functionality assays indicated a promoting effect of CFB in angiogenesis. Mechanistically, CFB exerts this pro-angiogenic effect by mediating the vascular endothelial growth factor (VEGF) signaling pathway. In summary, we demonstrate compelling evidence for the role of CFB in driving ocular angiogenesis in a VEGF-dependent manner. This work provides a framework for a more in-depth exploration of CFB-mediated effects in ocular angiogenesis in the future.

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Taohong Siwu-Containing Serum Enhances Angiogenesis in Rat Aortic Endothelial Cells by Regulating the VHL/HIF-1α/VEGF Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6610116 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Zhi Tang ◽

Wangyang Li ◽

Hongzan Xie ◽

Shengping Jiang ◽

Yunqing Pu ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Signaling Pathway ◽

Bone Repair ◽

Dependent Manner ◽

Sprague Dawley ◽

Aortic Endothelial Cells ◽

Vegf Signaling ◽

Vegf Signaling Pathway ◽

Aortic Endothelial

Background. The incidence of bone fracture and bone-related diseases is increasing every year. Angiogenesis plays a vital role in fracture healing and bone repair. This study assessed the benefits of Taohong Siwu (TSW) decoction on angiogenesis in isolated rat aortic endothelial cells (RAEC) treated with TSW-containing serum. Methods. The components of TSW decoction were analyzed by liquid chromatography-mass spectrometry (LC-MS). TSW-containing serum was prepared by gavage of TSW decoction to Sprague-Dawley (SD) rats. The effects of TSW-containing serum on the viability, migration, wound healing, and angiogenesis of RAEC were detected by the MTT, transwell, wound healing, and Matrigel lumen formation assays, respectively. In addition, the effects of an HIF-1α inhibitor on TSW-containing serum-induced RAEC were also assessed. The effects of TSW-containing serum on the expression of the HIF-1α signaling pathway were evaluated by qRT-PCR and western blot analysis. Results. LC-MS revealed that TSW decoction primarily contained isomaltulose, choline, D-gluconic acid, L-pipecolic acid, hypotaurine, albiflorin, and tryptophan. TSW-containing serum significantly increased the viability, migration, wound healing, and angiogenesis of RAEC in a dose-dependent manner. Furthermore, our results demonstrated that HIF-1α and VEGF expressions were increased in the cells of TSW-containing serum groups, whereas VHL expression was decreased. The effects of TSW-containing serum were reversed by treatment with an HIF-1α inhibitor. Conclusion. These results suggested that TSW decoction enhanced angiogenesis by regulating the VHL/HIF-1α/VEGF signaling pathway.

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The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1

AJP Renal Physiology ◽

10.1152/ajprenal.00428.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. F1284-F1294 ◽

Cited By ~ 9

Author(s):

Ming Wu ◽

Meihan Chen ◽

Ying Jing ◽

Junhui Gu ◽

Shuqin Mei ◽

...

Keyword(s):

Epithelial Cells ◽

Promoter Activity ◽

Dominant Negative ◽

Conditioned Media ◽

Complement Factor ◽

Dependent Manner ◽

Factor B ◽

Renal Epithelial Cells ◽

Complement Factor B ◽

M2 Phenotype

Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD.

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Splenic RNA and MicroRNA Mimics Promote Complement Factor B Production and Alternative Pathway Activation via Innate Immune Signaling

The Journal of Immunology ◽

10.4049/jimmunol.1502106 ◽

2016 ◽

Vol 196 (6) ◽

pp. 2788-2798 ◽

Cited By ~ 12

Author(s):

Lin Zou ◽

Yan Feng ◽

Ganqiong Xu ◽

Wenling Jian ◽

Wei Chao

Keyword(s):

Alternative Pathway ◽

Innate Immune ◽

Complement Factor ◽

Immune Signaling ◽

Factor B ◽

Complement Factor B ◽

Innate Immune Signaling ◽

Pathway Activation

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Coexistence of Closed and Open Conformations of Complement Factor B in the Alternative Pathway C3bB(Mg2+) Proconvertase

The Journal of Immunology ◽

10.4049/jimmunol.0902310 ◽

2009 ◽

Vol 183 (11) ◽

pp. 7347-7351 ◽

Cited By ~ 26

Author(s):

Eva Torreira ◽

Agustín Tortajada ◽

Tamara Montes ◽

Santiago Rodríguez de Córdoba ◽

Oscar Llorca

Keyword(s):

Alternative Pathway ◽

Complement Factor ◽

Factor B ◽

Complement Factor B

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Plasma protein expression profiles, cardiovascular disease, and religious struggles among South Asians in the MASALA study

Scientific Reports ◽

10.1038/s41598-020-79429-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Long H. Ngo ◽

M. Austin Argentieri ◽

Simon T. Dillon ◽

Blake Victor Kent ◽

Alka M. Kanaya ◽

...

Keyword(s):

Cardiovascular Disease ◽

Plasma Protein ◽

Expression Profiles ◽

South Asians ◽

Predictive Biomarkers ◽

Information Criteria ◽

Blood Protein ◽

Complement Factor ◽

Factor B ◽

Complement Factor B

AbstractBlood protein concentrations are clinically useful, predictive biomarkers of cardiovascular disease (CVD). Despite a higher burden of CVD among U.S. South Asians, no CVD-related proteomics study has been conducted in this sub-population. The aim of this study is to investigate the associations between plasma protein levels and CVD incidence, and to assess the potential influence of religiosity/spirituality (R/S) on significant protein-CVD associations, in South Asians from the MASALA Study. We used a nested case–control design of 50 participants with incident CVD and 50 sex- and age-matched controls. Plasma samples were analyzed by SOMAscan for expression of 1305 proteins. Multivariable logistic regression models and model selection using Akaike Information Criteria were performed on the proteins and clinical covariates, with further effect modification analyses conducted to assess the influence of R/S measures on significant associations between proteins and incident CVD events. We identified 36 proteins that were significantly expressed differentially among CVD cases compared to matched controls. These proteins are involved in immune cell recruitment, atherosclerosis, endothelial cell differentiation, and vascularization. A final multivariable model found three proteins (Contactin-5 [CNTN5], Low affinity immunoglobulin gamma Fc region receptor II-a [FCGR2A], and Complement factor B [CFB]) associated with incident CVD after adjustment for diabetes (AUC = 0.82). Religious struggles that exacerbate the adverse impact of stressful life events, significantly modified the effect of Contactin-5 and Complement factor B on risk of CVD. Our research is this first assessment of the relationship between protein concentrations and risk of CVD in a South Asian sample. Further research is needed to understand patterns of proteomic profiles across diverse ethnic communities, and the influence of resources for resiliency on proteomic signatures and ultimately, risk of CVD.

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