The role of complement activation fragments in hypertension
Complement activation leads to generation of cleavage fragments like the
opsonin and the anaphylatoxins C3a and C5a. The role of anaphylatoxins
in hypertension has been reviewed recently by us (Wenzel et al., 2017)
and we will only briefly summarize current findings. Zhang et al.reported increased levels of C5a in humans with high blood pressure. In
line with this, Infusion of Ang II causing arterial hypertension led to
increased systemic anaphylatoxin generation in mice (Zhang et al.,
2014a). Conversely, C5a receptor 1 (C5aR1) deficient mice exhibited
markedly reduced cardiac remodeling and inflammation after Ang II
infusion. Similarly, pharmacological inhibition of C5a production by an
anti-C5 monoclonal antibody or C5aR1 targeting with an inhibitor (PMX53)
recapitulated the effects of C5aR1 deficiency (Zhang et al., 2014a;
Zhang et al., 2014b). Bone marrow chimera experiments revealed that
C5aR1 expression on bone marrow–derived, and not vascular, cells was
critical in mediating Ang II–induced cardiac injury and remodeling
(Zhang et al., 2014a). The key role of C5aR1 as a disease driver was
also confirmed in a rat model: Treatment of deoxycorticosterone acetate
(DOCA) salt hypertensive rats with the C5aR1 antagonist PMX53 attenuated
endothelial dysfunction and decreased hypertensive cardiac injury. PMX53
treatment resulted in less ventricular collagen deposition and
hypertrophy as compared with untreated hypertensive rats, whilst C5aR1
antagonism did not change systolic blood pressure (Iyer et al., 2011).
We also found such a blood pressure-independent nephroprotective effect
of C5aR1 deficiency in an accelerated model of hypertension in mice
(Weiss et al., 2016). Moreover, using a C5aR1 reporter mouse in a
hypertension model, expression of C5aR1 in the kidney was shown on
dendritic cells as well as in monocytes/ macrophages and granulocytes.
No expression was detected on resident cells in the heart or the aorta
of these animals. However, in contrast to the work of Zhang et
al., cardiac injury was accelerated in C5aR1 deficient mice with
significantly increased cardiac fibrosis and heart weight in C5aR1
deficient mice after Ang II infusion. The reason for the difference
between cardiac and renal injury is currently unclear. These
observations indicate that the C5a:C5aR1 axis drives end organ damage in
the kidney, while its exact role in cardiac injury remains controversial
and needs to be further explored. The role of the alternative second C5a
receptor (C5aR2) in hypertension is unknown. In C3a receptor (C3aR)
deficient mice, Zhang et al. observed a trend for increased
cardiac injury when compared to wild type mice after Ang II infusion
(Zhang et al., 2014a; Zhang et al., 2014b) Similarly, preliminary data
from our laboratory suggest an enhanced renal injury in C3aR deficient
mice after Ang II infusion. A protective role for the C3aR in
hypertension would align with the emerging concept that C3a has more
dominant activity in the maintenance of cell homeostasis and/ or return
to this homeostasis after tissue activation over C5a (West et al.,
2020).
The presence of complement receptor expression infiltrating immune cells
mostly in kidney suggests that these cells mediate some of the
pathology. Indeed, an important role for T cells in hypertension was
shown in 2007, when it was found that the increase in blood pressure
caused by Ang II infusion was significantly blunted in mice – deficient
for the recombinase-activating gene 1
(Rag-1–/– mice) – which are lacking for T
and B cells. In further experiments, it was shown that the adoptive
transfer of T cells restored the hypertensive response, indicating that
T cells play an important role in generation of arterial hypertension.
However, the contribution of T cells to hypertension has recently been
challenged by work from different groups including ours that could not
confirm increased resistance of Rag-1 deficient mice to Ang II
infusion (Ji et al., 2017; Seniuk et al., 2020). However, T cell
response are highly diverse in nature and these contradictive findings
could indicate that we need a better understanding of the exact nature
of the T cell responses evoked during disease induction and progression.
For example, an important subgroup of T cells are regulatory T cells
(Tregs) a subpopulation of CD4+ T cells with CD25 and
Foxp3 positivity. The main function of Tregs is maintenance of
immunological tolerance. Several groups have shown that adoptive
transfer of Tregs lowers blood pressure and ameliorates cardiac and
renal injury in different models of hypertension (summarized in (Wenzel
et al., 2016)). The anaphylatoxins are known as regulators of Treg
activity: C3a/C3aR and C5a/C5aR inhibit the function of
CD4+Foxp3+ circulating Tregs (Kwan
et al., 2013) and absence of C3aR and C5aR signals in
CD4+ T cells induces spontaneous
Foxp3+ Treg differentiation upon T cells activation.
Also, activation of CD4+ T cells from mice deficient
in both C3aR and C5aR leads to a greater abundance of the
anti-inflammatory cytokines like IL-10 and TGF-β1 produced by these
cells (Strainic et al., 2013). Chen et al . have recently shown in
a series of elegant experiments that Ang II–induced hypertension
resulted in an elevated expression of C3aR and C5aR in
Foxp3+ Tregs. C3aR and C5aR double deficiency
decreased blood pressure in response to angiotensin II compared with
wild type mice via activating Foxp3+ Tregs. Adoptive
transfer of C3aR and C5aR double deficient Tregs showed a more profound
protective effect against Ang II–induced blood pressure elevation and
renal damage when compared to wild type Treg transfer. Depletion of
Tregs with CD25 neutralizing antibodies abolished the protective effects
(Chen et al., 2018). However, Chen et al . found that high blood
pressure reduced the number of Tregs compared to normotensive mice. This
is unusual since the number of Tregs in the kidney at least in models of
accelerated hypertension is increased in our own work (Krebs et al
2014). Clearly, more work has to be done to explain the fascinating
observation and mechanisms that deficiency of C5aR1 and C3aR lowers
blood pressure by upregulating Tregs.