Abstract: SA-PO339
Deficiency of the Anaphylatoxin Receptors C5aR2 and C3aR Aggravates Hypertensive Renal Injury
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Bode, Marlies, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
- Meyer-Schwesinger, Catherine, University of Hamburg, Hamburg, Germany
- Kurts, Christian, Institute of Experimental Immunology, Bonn, Germany
- Ehmke, Heimo, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Koehl, Joerg, University of Luebeck, Luebeck, Germany
- Wenzel, Ulrich O., University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
Background
Complement drives the host defense against microbes and mediates inflammatory responses. In addition, recent data also support a role for complement in arterial hypertension.
During the activation and amplification of the complement cascade, the anaphylatoxins C3a and C5a are released and trigger pro inflammatory signaling via their corresponding receptors. We recently described that C5a receptor 1 deficiency ameliorated hypertensive renal injury. However, the role of the second C5a receptor (C5aR2) and the C3a receptor (C3aR) in hypertension and hypertensive end organ damage remain unclear.
Methods
Expression of C5aR2 and C3aR on infiltrating and resident renal cells were determined using tandem tomato reporter mice for either C3aR or C5aR2 by flow cytometry and confocal microscopy. The hypertension model of angiotensin II infusion in combination with unilateral nephrectomy and high salt diet was induced in Balb/c wildtype, C5aR2- and C3aR-deficient mice. The glomerular filtration rate (measured with fitc sinistrin), albuminuria and glomerular damage were determined.
Results
Flow cytometric analysis of leukocytes isolated from the kidney of anaphylatoxin reporter mice showed C5aR2 expression on dendritic cells (34%), macrophages (30%) and neutrophils (14%) whereas dendritic cells are the major C3aR-expressing population (90%). C5aR2 and C3aR were also detected by confocal microscopy in the kidney only on infiltrating cells.
Both anaphylatoxin receptor-deficient mice suffered from markedly increased renal injury after Ang II infusion with higher albuminuria, glomerular filtration rate and glomerular injury compared to hypertensive wildtype mice. The mortality in hypertensive C3aR-deficient mice was significantly higher than that observed in hypertensive wildtype or C5aR2-deficient mice and was associated with increased bleeding.
Conclusion
Our findings identify C5aR2 and C3aR expression on infiltrating (mainly dendritic cells, macrophages and neutrophils) but not on resident cells in the kidney. C5aR2 or C3aR deficiency was associated with strongly increased renal injury in response to arterial hypertension. Together, we propose that C5aR2 and C3aR mediate protective or homeostatic effects in hypertensive renal injury.
Funding
- Government Support - Non-U.S.