A1197 Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II-Induced Hypertension via Regulatory T Cells

Abstract

Objectives: We aim to determine whether complement C3a receptor (C3aR) and C5a receptor (C5aR) could regulate BP via modulating regulatory T cells (Tregs). Methods: We used C3aR and C5aR double knockout (DKO) mice and performed angiotensin II (Ang II)-induced hypertension. Results: C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic BP in response to Ang II compared to wild type (WT), single C3aR deficient (C3aR−/−) or C5aR deficient (C5aR−/−) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared to WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Conclusion: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.