C5aR expression in kidney tubules, macrophages and fibrosis

The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of C5aR and a second C5a receptor C5L2 by using immunohistochemistry, in situ hybridization, and spatial gene expression on formalin-fixed, paraffin-embedded human and mouse kidney. C5aR was detected on interstitial macrophages and in multiple tubular regions, including distal and proximal; C5L2 had a similar expression pattern. The 5/6 nephrectomy model of chronic kidney injury exhibited increased C5aR expression by infiltrating cells within the fibrotic regions. C5aR expression was confirmed on human leukocytes and in vitro differentiated macrophages by flow cytometry, and treatment with C5a induced the expression of chemokines and remodeling factors by macrophages, including CCL-3/-4/-7, -20, MMP-1/-3/-8/-12, and F3, and promoted leukocyte survival. C5a activity was C5aR dependent, as demonstrated by reversal with the C5aR inhibitor avacopan. Collectively, these results suggest that myeloid C5aR may induce excessive inflammation in the kidney via immune cell recruitment, extracellular matrix destruction, and remodeling, resulting in fibrotic tissue deposition.