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.