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.

C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis

“…In addition to the generation of autoimmunity, signaling through C5aR1 may also contribute to the perpetuation of nephritogenic autoimmunity that occurs in active disease after MPO deposition in the kidney, which is a site enriched for C5aR1-expressing APCs. 42 The production of ANCA is essential for the pathogenesis of AAV. We observed that MPO-ANCA titers were reduced in immunized C5aR1 À/À mice; this supports the role for the C5aR1 in promoting humoral immunity to other antigens seen in previous studies.…”

Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility

“…Collectively, these studies show that C5a-C5aR1 signalling is involved in renal disease initiation and progression via changes in mitochondrial agility, specifically through changes in cardiolipin remodelling, mitochondrial metabolite flux and mitochondrial respiratory function.Although the liver is the primary site of complement synthesis (40), local production of complement in the kidney, particularly within renal tubules could contribute to tissue injury in a variety of renal diseases(41). C5aR1 has been shown to be expressed on proximal tubular cells(42), podocytes(43), fibroblasts(44), mesangial cells, vascular endothelial and smooth muscle cells(11). Genome-wide transcriptome analysis showed upregulation of the complement pathway in microdissected human renal glomerular and tubule samples from patients with DKD(45).…”

The role of complement in arterial hypertension and hypertensive end organ damage

“…PMX53 treatment resulted in less ventricular collagen deposition and hypertrophy as compared with untreated hypertensive rats, whilst C5aR1 antagonism did not change systolic blood pressure (Iyer et al, 2011). We also found such a blood pressure-independent nephroprotective effect of C5aR1 deficiency in an accelerated model of hypertension in mice (Weiss et al, 2016). Moreover, using a C5aR1 reporter mouse in a hypertension model, expression of C5aR1 in the kidney was shown on dendritic cells as well as in monocytes/ macrophages and granulocytes.…”