title: The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.
abstract: Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Alva
authors.initials: A
authors.lastname: Rosendahl
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Czesla
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.affiliation: Department of Cellular and Integrative Physiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, Rheinische Friedrich-Wilhelms University, Bonn, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Leibniz Institute for Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany;
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: Institute for Systemic Inflammation Research, Lübeck, Germany, and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany; wenzel@uke.de.
authors.forename: Ulrich O
authors.initials: UO
authors.lastname: Wenzel
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*
chemical_list: C000591759:C5ar1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D000804:Angiotensin II
keywords: C5aR1; albuminuria; angiotensin II; cardiac damage; renal damage