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

Abstract

The role of CX₃CR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CX₃CR1 in hypertensive renal and cardiac injury. Expression of CX₃CR1 was determined using CX₃CR1^GFP/+ mice that express a green fluorescent protein (GFP) reporter in CX₃CR1⁺ cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45⁺ cells expressed CX₃CR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CX₃CR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g^-1·min^-1) and a high-salt diet in wild-type ( n = 15) and CX₃CR1-deficient mice ( n = 18). CX₃CR1 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, CX₃CR1-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 were not different between both genotypes. Our findings suggest that CX₃CR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CX₃CR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

Keywords: CXCR1; albuminuria; angiotensin II; cardiac damage; podocyte; renal damage.