Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension

Abstract

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.

Blocking the CCL2–CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model

“…Additionally, CCR2 inhibitors showed anti-inflammatory effects in the animal models with different diseases such as diabetic nephropathy (27), kidney hypertension (28), steatohepatitis (29), renal atrophy (30) models and no adverse effects were reported. We decided to test whether treatment of mice with a CCR2-specific inhibitor could reduce liver inflammation in KO mice.…”

Development of renal atrophy in murine 2 kidney 1 clip hypertension is strain independent

“…We characterized three different genetically unmodified strains of mice that are commonly employed to study renal disease progression in other experimental systems: C57BL/6J (N=205 RAS, N=116 sham), C57BLKS/J (N=129 RAS, N=48 sham) and 129Sv (N=112 RAS, N=44 sham) mice. Some of these animals served as controls in previously published studies (43 of 156 129Sv mice (Warner et al, 2012), 23 of 321 C57BL/6J mice (Wang et al, 2013), and 162 of 177 C57BLKS/J mice (Hartono et al, 2013, 2014; Kashyap et al, 2016). Additional mice, reported here, were used to support our ongoing studies to further characterize the 2 kidney 1 clip model and to define basic mechanisms of renal disease progression in this model.…”

The role of chemokines in hypertension and consequent target organ damage

“…In mice, established hypertension caused by mineralocorticoid receptor activation in combination with salt loading is partially reversed by the administration of a CCR2 inhibitor (30). By contrast, CCL2 inhibition exacerbates renovascular hypertension, a model in which reduced perfusion to the clipped kidney drives renin secretion (31). …”

“…In the hypertensive kidney, CCR2 similarly drives macrophage infiltration, local oxidative stress, glomerular injury, and ultimately loss of glomerular filtration rate during renin-angiotensin system (RAS) activation (29, 32). Accordingly, CCL2 inhibition attenuates macrophage infiltration and fibrosis in the Goldblatt hypertensive kidney (31). Collectively, these studies illustrate that local macrophage accumulation via the CCL2/CCR2 axis is a principal mediator of vascular remodeling and kidney injury in hypertension.…”