Deficiency of complement C3a and C5a receptors does not prevent angiotensin II–induced hypertension and hypertensive end-organ damage

Complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on tissue integrity. Recently it was suggested that hypertension is a disease characterized by a decreased number of forkhead box protein 3 (Foxp3) + regulatory T cells (Tregs) and that combined deficiency of the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) upregulates Tregs and heals hypertension and hypertensive end-organ damage. Using data from the European Renal cDNA Bank, renal single cell sequencing data and immunohistochemistry we found increased expression of C3aR, C5aR1 and Foxp3 in kidney biopsies of patients with hypertensive nephropathy. Expression of C3aR and C5aR1 was mainly found in myeloid cells and almost absent in lymphocytes. Next we aimed to determine whether C3aR or C3aR/C5aR1 double deficiency decreases blood pressure and hypertensive injury in Ang II infused mice. However, no difference was found for blood pressure, renal injury (albuminuria, glomerular and tubulointerstitial injury, inflammation) and cardiac injury (cardiac fibrosis, heart weight, gene expression) between C3aR KO and WT mice as well as C3aR/C5aR1 double KO respectively. Ang II as well as DOCA salt induced hypertension resulted in an increased number of Tregs in the kidney. This was valid in mice of the Balb/c and C57black strain. In summary, hypertensive nephropathy in patients is characterized by an increased expression of anaphylatoxin receptors and Tregs. However, deficiency of C3aR alone or C3aR and C5aR1 combined does not influence blood pressure or hypertensive end-organ damage in Ang II induced hypertension. Targeting the anaphylatoxin receptors C3aR alone or in combination with C5aR1 is not useful to treat cardiovascular disease in hypertension.