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.