DEFICIENCY OF COMPLEMENT C3A AND C5A RECEPTORS DOES NOT PREVENT ANGIOTENSIN II–INDUCED HYPERTENSION AND HYPERTENSIVE END ORGAN DAMAGE

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Objective: Complement activation may play an important role in pathophysiology of hypertension and associated end organ damage through its effect on tissue integrity and immune responses. The anaphylatoxins C3a and C5a are highly active effectors of the complement system operating through binding to their receptors C3a3R and C5aR1. Recently it was suggested that regulatory T cells (Tregs) are downregulated in hypertension and that combined deficiency of C3aR and C5aR1 in lymphocytes upregulates Tregs and heals hypertension (Circ Res 122: 970-983, 2018). Design and method: To further address the role of C3aR, C5aR1 and Tregs in human and murine hypertension we used data from the European Renal cDNA Bank, renal single cell sequencing and renal immunohistochemistry of hypertensive patients. Results: Expression of C3aR and C5aR1 was mainly found in myeloid cells and almost absent in lymphocytes and resident renal cells. An increased expression of C3aR, C5aR1 as well as forkhead box protein 3 (FoxP3), a known marker for Tregs, was found in the kidney in hypertension. Next we determined whether C3aR deficiency or C3aR/C5aR1 double deficiency decreases blood pressure and hypertensive injury in angiotensin (Ang) II infused mice. No difference was found for blood pressure, renal injury (glomerular filtration rate, albuminuria, glomerular and tubulointerstitial injury, inflammation) and cardiac injury (cardiac fibrosis, heart weight, gene expression) between C3aR knockout and wildtype mice as well as C3aR/C5aR1 double knockout respectively. Ang II as well as DOCA salt induced hypertension resulted in an increased number of Tregs in the kidney. Isolation of a very pure (>99%) Treg population from a RORC x FIR double fluorescence reporter mouse revealed low abundance of C3aR and absence of C5aR1 in murine Tregs. Conclusions: In summary, hypertensive nephropathy in patients and mice 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. Targeting the anaphylatoxin receptors C3aR alone or in combination with C5aR1 is not useful to treat cardiovascular disease in hypertension.