Boyilla, Rajendra

CX3CR1 is a chemokine receptor widely expressed on inflammatory cells which recognizes CX3CL1 (fractalkine) a membrane bound chemokine that can function as an adhesion receptor. Blockade of CX3CR1 has been shown to reduce inflammation and chronic renal injury in a variety of models. We sought to determine whether CX3CR1 deficient mice are protected from chronic renal injury in experimental renal artery stenosis (RAS). RAS was established in CX3CR1 knockout (KO) and wild‐type C57BLK/6 mice (WT) through placement of a cuff on the right renal artery. Sham mice underwent manipulation of the right renal artery without placement of a cuff. As assessed by MRI, mean flow reduction was 65.3% in the WT mice and 66.5% in the KO mice (p=ns) subjected to RAS. Both KO and WT mice developed hypertension, which persisted throughout the 4 week study. KO and WT mice developed a similar degree of cardiac hypertrophy (166 mg WT, 172 mg KO, p=ns; 117 mg sham). Stenotic kidney weights were reduced to a similar extent in KO and WT mice (sham 148 mg, WT 83 mg, KO 53 mg) with compensatory hypertrophy of the contralateral kidney (sham 136 mg, WT 170 mg, KO 206 mg, p=0.0016 KO vs WT). The stenotic kidney of both KO and WT mice developed severe atrophy, characterized by flattening and simplification of tubular epithelium and influx of interstitial T cells and macrophages (32.8 % cortical surface area for WT and 76.4% cortical surface area for KO, p=0.01). The contralateral kidney was without significant histopathologic abnormality. We conclude that development of severe atrophy is not prevented in CX3CR1 KO mice, indicating that alternative pathways contribute to chronic renal damage in this model. Support or Funding Information This work is supported by NIH Grant R01 AI100911.

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.