The role of distinct complement pathways in hypertension
Classical pathway —the classical pathway may be considered a target when antibody mediated complement activation is involved in disease pathogenesis. Indeed, recent data suggest that also B cells/IgGs are crucial for the development of Ang II–induced hypertension and vessel remodeling in mice (Chan et al., 2015). Recent findings demonstrate a key role for complement C1-induced activation of β-catenin signaling in vascular remodeling and hypertension (Sumida et al., 2015). C1q activates beta-catenin signaling by binding to Frz and cutting Lrp5/6 with C1r/s, which is independent of Wnt ligands in aorta as well as skeletal muscle (Naito et al., 2012; Sumida et al., 2015). Ang II infusion raises blood pressure, promotes arterial remodeling characterized by vascular smooth muscle cell (VSMC) proliferation and upregulates the expression of Wnt/β-catenin target genes. Pharmacologic or genetic inhibition of β-catenin signaling suppresses VSMC proliferation without lowering blood pressure. Ang II infusion recruits macrophages into the aorta, and these macrophages secrete the complement component C1q. Depletion of macrophages, administration of a C1 inhibitor or genetic ablation of C1q suppresses Ang II-induced activation of β-catenin signaling and VSMC proliferation, identifying macrophage-secreted complement C1 as an inducer of β-catenin signaling and VSMC proliferation in hypertensive arterial remodeling. However, no effect on blood pressure is found (Wenzel et al., 2017).
Lectin pathway —the lectin pathway is evolutionarily older than the classical pathway and is more complex. Five lectin pathways-related pattern recognition proteins have been identified so far, including mannose-binding lectin (MBL), the ficolins 1 – 3 and collectin 11. These pattern recognition proteins detect different carbohydrate and/or acetylation patterns expressed generally by pathogens or stressed and dying host cells and circulate in complex with MBL-associated serine proteases (Ricklin et al., 2018). Hemodynamic factors including shear stress and hypertensive factors like angiotensin II, salt or aldosterone induce subtle injuries and damage cells, which then leads to the release of molecules called the Damage-Associated Molecular Patterns (DAMPs). These can the activate lectin pathway-derived sensors as well as other innate immune sensor systems such as the toll-like receptors (TLRs) and probably some inflammasome (Krishnan et al., 2014).
Alternative pathway – The alternative complement pathway has a critical role in amplifying the complement response independent of the initiating pathway and hence in exacerbating inflammatory pathologies. Healthy human cells are protected from the effects of the alternative pathway activation and subsequent C3/C5 convertase formation by a series of inhibitors of the regulator of complement activation family (Ricklin et al., 2018). The alternative pathway is primarily responsible for the rapid amplification of opsonisation on unprotected cells and provides a means of constant background activity. Deficiency of protective inhibitors plays a driving role in thrombotic microangiopathies that have similarities with malignant nephrosclerosis (Wenzel et al., 2017). It is therefore expected that the alternative pathway plays a role in hypertensive end organ damage and this is currently explored in the field.