Summary and outlook
The gravest consequence of chronic hypertension is end organ damage. In several experimental models in which complement proteins or their receptors are eliminated, target organ damage is reduced – however, in most studies blood pressure is not or only modestly reduced. Thus, albeit a wealth of work indicating strongly that the complement system is also involved the more immediate effects of hypertension, we know little about the underlying complement-mediated mechanisms (Figure 4). C1q, C3, C5, C3aR C5aR1 have been examined and their effect on blood pressure, cardiac, renal or vascular injury are solid, but again, how exactly their impact is generated, is unclear (Figure 4). Furthermore, many of the complement components have not been probed yet for potential disease involvement. For example, no data are available on the role of C5aR2 in hypertension, and nothing is known about the contributions of CD55, CD46 or other direct complement regulators to hypertension. Also, the impact of complement on other hypertension-related complications such hypertensive brain injury, malignant nephrosclerosis or endothelial dysfunction are either not explored yet or ill defined.
While blood pressure lowering is clearly important to reach this goal, prevention of local inflammation that accompanies hypertensive end organ damage should also to be addressed. Since complement has pro- as well as anti-inflammatory functions, complete inhibition of the canonical complement cascade may result in unwanted effects in arterial hypertension. Thus, if we want to harness the potential of the complement system in the design of novel therapeutic approaches to combat hypertension, renal, and cardiovascular diseases, we need to understand the exact spatial, temporal and cellular contributions of complement to these disease pathologies.
Based on what we know today this will likely require a holistic approach that ideally integrates large data set analyses about genetic complement variations in patients and the functional probing of intracellular and extracellular complement as well as its crosstalk with other (innate) immune sensors.