Non-canonical C3 activation in hypertension
Békássy et al. have recently shown that renin cleaves C3 into C3b and
C3a, in a manner identical to the C3 convertase (Bekassy et al., 2018).
Cleavage was inhibited by the renin inhibitor aliskiren. If this occurs
also in vivo, it would be a missing link by which the
renin-angiotensin system triggers the alternative pathway. This
mechanism initiates complement activation, with specific tropism for the
kidney, because renin concentrations are higher in the kidney than in
the systemic circulation. Renin-angiotensin system blockade by an AT1
antagonist or an ACE Inhibitor induces a rise in renin. This could
indicate that renin-angiotensin system blockade without renin inhibition
could have an adverse effect in complement-mediated kidney disease.
However, this intriguing possibility needs to be still proven forin vivo relevance.
Recently, a case of atypical hemolytic uremic syndrome (aHUS) with
malignant hypertension and end-stage renal disease was reported in which
high dosed renin inhibitor aliskiren added together with eculizumab
improved clinical parameters of the patients suggesting that the use of
high-dose aliskiren as an adjunct therapy in a patient treated with
eculizumab for aHUS (Plasse et al., 2020). This is possibly an exciting
therapeutic advance, but raises almost more questions than it does
provide answers. For example, what is the relative contribution of renin
to local kidney C3 activation? The C5 inhibitor eculizumab is currently
used to treat complement-related kidney conditions such as aHUS. Does
conventional renin-angiotensin system blockade interfere with optimal
outcomes in complement-related disease? If renin-angiotensin system
blockade results in renin release, why is there a large body of evidence
supporting renin-angiotensin system blockade as a key nephroprotective
maneuver even in nephropathies that may be complement-mediated? Do
renin-secreting tumors develop complement activation? Do angiotensinogen
and C3 compete for renin? And, above all, should aliskiren become the
renin-angiotensin system blocker of choice for complement-mediated
kidney disease (Perez-Gomez & Ortiz, 2020)? Future work will hopefully
providing answers to these questions.