Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II–Induced Hypertension and Hypertensive End-Organ Damage

Background: Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3 + (forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension. Methods and Results: Using data from the European Renal cDNA Bank, single-cell sequencing and immunohistochemistry, we found increased gene expression of C3aR, C5aR1, and Foxp3 as well as an increased number of positive cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in 2 models of Ang (angiotensin) II–induced hypertension in mice. As such, no differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned. Irrespectively of the mouse strain used, the number of renal regulatory T cells was not decreased in Ang II as well as in deoxycorticosterone salt induced hypertension. Conclusions: Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II–induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.