The chemokine receptor CX₃CR1 reduces renal injury in mice with angiotensin II-induced hypertension

Abstract

The role of CXCR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CXCR1 in hypertensive renal and cardiac injury. Expression of CXCR1 was determined using CXCR1 mice that express a GFP reporter in CXCR1 cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45 cells expressed CXCR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%) and T cells (10%). Using confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CXCR1 in hypertensive end-organ injury an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of Ang II (1.5 ng/g/min) and a high salt diet in wildtype (n=15) and CXCR1-deficient mice (n=18). CXCR1-deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80 macrophages and CD11b/Ly6G neutrophils in Ang II infused mice. Surprisingly, CXCR1-deficient mice exhibited increased albuminuria, glomerular injury and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis and expression of fetal genes and matrix components was not different between both genotypes. Our findings suggest that CXCR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CXCR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

Ambulatory blood pressure in patients with systemic lupus erythematosus: Association with markers of immune activation

“…For example, fractalkine (CX3CL-1) has been implicated in the pathogenesis of hypertension 40 and hypertension-related renal injury. 41 Our finding that this chemokine was associated with nocturnal systolic BP, diastolic BP, and percent nocturnal dip suggests that CX3CL-1 is not only a therapeutic target for multiple inflammatory conditions, 42 but also a potential therapeutic target for hypertension.…”

Regulation and function of CX3CR1 and its ligand CX3CL1 in kidney disease

“…While some studies suggest profibrotic action after ischemia reperfusion injury (Furuichi et al 2006 ) and more recently, after oral fructose treatment (Yu et al 2018 ), both pro- and antifibrotic effects of genetic CX3CR1 deletion were reported in unilateral ureteral obstruction in mice (Engel et al 2015 ; Peng et al 2015 ). Also in kidney fibrosis induced by hypertension, while an earlier report describes aggravation by CX3CR1 in DOCA salt–treated mice (Shimizu et al 2011 ), a more recent study found less renal hypertensive damage in unilaterally nephrectomized angiotensin II-infused mice on a high salt diet in the presence of CX3CR1 than in its absence (Ahadzadeh et al 2018 ). There was no difference in cardiac fibrosis.…”

Potential biomarkers reflecting inflammation in patients with severe periodontitis: Fractalkine (CX3CL1) and its receptor (CX3CR1)

“…The authors of the study speculated that CX3CR1 has a protective role against liver fibrosis via infiltrating monocytes in the injured liver. Although CX3CL1/CX3CR1 axis has been linked to pathogenesis of chronic inflammatory diseases, there are some studies also that showed the anti‐inflammatory features of CX3CR1 29,30 . Considering this information, we may suggest that elevated levels of CX3CR1 in serum may reflect homeostasis without binding its ligand, CX3CL1.…”