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.