CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension

Abstract

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg−1·day−1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.

Melatonin Prevents T Lymphocyte Infiltration to the Kidneys of Hypertensive Rats, Induced by a High-Salt Diet, by Preventing the Expression of CXCR3 Ligand Chemokines

“…A HSD increased CCL3's expression, but no reduction was detected in the melatonin treated rats. A recent study in the same model has shown that a HSD upregulates CCL2 in the kidney by using the RNA-Seq method [39]. However, this study tested the levels on days 3 and 21 after the diet started.…”

Transcriptional profile changes after treatment of ischemia reperfusion injury-induced kidney fibrosis with 18β-glycyrrhetinic acid

“…Alsheikh et al. demonstrated that CCL2/CCR2 was important in the early recruitment of leukocytes in rat hypertension kidney damage model [ 31 ]. In a clinical setting, Puthumana et al.…”

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension

“…This observation as well as the corresponding increase of M1 macrophage infiltration was to be expected from previous reports from the same model [ 13 ]. Others have previously shown that blockade or deficiency of CCL2 ameliorates mononuclear cell infiltration and target organ damage in renovascular or other forms of hypertension [ 30 , 31 ]. These data are certainly compatible with a role for macrophage infiltration in the development of malignant hypertension, but the parallel increase of M2 macrophage infiltration should not be overlooked.…”