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.