Kidney Week

Abstract: TH-PO201

Role of Anaphylatoxin Receptors C5aR1 and C5aR2 in Hypertension and Hypertensive End-Organ Damage

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Dreher, Leonie, III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Leonie Dreher, MD

• Walachowski, Sarah, Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States

Sarah Walachowski, PhD

• Herrnstadt, Georg Rudolf, III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Georg Rudolf Herrnstadt, MD

• Ehnert, Nicolas, III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Nicolas Ehnert

• Meyer-Schwesinger, Catherine, Department of Cellular and Integrative Physiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Catherine Meyer-Schwesinger, MD

• Koehl, Joerg, Institute for Systemic Inflammation Research, University Hospital Schleswig-Holstein, Lübeck, Germany

Joerg Koehl, DrMed

• Huber, Tobias B., III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Tobias B. Huber, MD, FASN

• Bosmann, Markus, Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States

Markus Bosmann, MD

• Wenzel, Ulrich O., III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Ulrich O. Wenzel, MD

Group or Team Name

• AG Wenzel.

Background

Elevated blood pressure induces activation of the complement system. The anaphylatoxin C5a, a major inflammatory effector of the complement system, binds to the C5a receptor 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1 knockout (KO) mice have reduced hypertensive renal injury. However, the role of the second C5a receptor and the extent of functional overlap between C5aR1 and C5aR2 remains enigmatic. We set out to examine the role of the C5aR2 and potential additional beneficial or antagonistic effects of combined deficiency of C5aR1 and C5aR2.

Methods

With single cell RNA sequencing we addressed the expression of C5aR2 in patients with hypertensive nephropathy. Murine expression of the C5aR2 was examined using a tandem dye Tomato-C5aR2 reporter mouse. For further investigation we used an aggravated model of hypertension with unilateral nephrectomy, infusion of angiotensin (Ang) II and high salt diet in both C5aR2 KO and mice with double deficiency of C5aR1 and C5aR2 (C57BL/6J-Del(7C5ar2-C5ar1)1Bosm; generated by CRISPR/Cas9 guided editing).

Results

Main expression of C5aR2 was found in myeloid cells in human kidneys with increased expression in hypertensive patients. Flow cytometric analysis of leucocytes isolated from kidneys of the tandem dye Tomato-C5aR2 reporter mice also showed main expression in myeloid cells. The expression pattern was comparable to that of C5aR1.
No differences in blood pressure and renal injury (albuminuria, GFR, glomerular and tubulointerstitial injury) between hypertensive wildtype (WT) and C5aR2 KO (n=14) or C5aR1xC5aR2 KO (n=24) mice were found. To examine whether the effects are specific for Ang II induced hypertension, we also induced deoxycorticosterone acetate (DOCA) salt hypertension for 6 weeks in WT and C5aR1/2-deficient mice (n=12). Consistent with the findings in Ang II induced hypertension no significant differences regarding blood pressure or renal injury were found also in DOCA salt hypertension.

Conclusion

Both, C5aR1 and C5aR2 are mainly expressed on myeloid cells in humans and mice. While C5aR1 deficiency is potentially beneficial in hypertensive renal injury, deficiency of C5aR2 alone or in combination with C5aR1 has no effect on blood pressure and hypertensive end organ damage.

Funding

• Government Support – Non-U.S.