Role of the MCP‐1/CCR2 Axis in the Development of Dahl Salt‐Sensitive (SS) Hypertension and Renal Damage

Abstract

Studies examining mechanisms of SS hypertension have implicated the infiltration of immune cells into the kidneys which contribute to elevated blood pressure and associated renal damage. However, the signaling pathways by which immune cells traffic to the kidneys remain poorly understood. The present set of studies were performed to test the hypothesis that the MCP‐1/CCR2 pathway contributes to the development of hypertension and renal damage in Dahl‐SS rats fed a high salt diet by modulating renal immune cell infiltration. Monocyte Chemoattractant Protein‐1 (MCP‐1) was nominated from a transcriptomic study of kidneys from Dahl‐SS rats fed either a Low Salt (LS‐0.4% NaCl) or a High Salt (HS‐4.0% NaCl) diet. Of all the chemokines examined, MCP‐1 was one of only two significantly upregulated in kidneys following HS diet. As measured by ELISA, initial experiments demonstrated increased urinary excretion of MCP‐1 in Dahl‐SS rats switched from a LS to a HS diet within seven days of HS (11.2±1.3 vs 1.6±0.4 μg/24hr at LS baseline, n=4/group), while there was no difference in serum. To test the functional role of MCP‐1 in SS hypertension, seven‐week‐old male Dahl‐SS rats maintained on a LS diet were instrumented with radio‐telemeters for continuous measurement of blood pressure. After 1 week of recovery, LS baseline blood pressure was measured for 1 week and then the rats were switched to HS and randomly divided into two groups (n=6/group) to receive daily intraperitoneal shots of either CCR2 (MCP1 receptor) antagonist (RS102895 at 5mg/kg/day in DMSO) or DMSO vehicle for 3 weeks. Overnight urine collections were performed at baseline and then weekly until the conclusion of the study. While LS baseline mean arterial pressure (MAP) was similar in both groups (124.7±2.2 vs 124.1±1.7 mmHg in vehicle group), the rats receiving CCR2 antagonist had significantly blunted hypertension after 3 weeks of HS diet compared to the vehicle group (146.3±4.1 vs 160.1±7.3 mmHg respectively), p‐value<0.001 by two‐way ANOVA. This protection was mirrored in the urinary albumin excretion rate where both groups had comparable LS baseline levels (12.6±4.4 vs 16.3±4 mg/24hr in vehicle group), but the CCR2 antagonist group had significantly lower albumin excretion rate after 3 weeks of HS diet compared to vehicle (42.2±8.3 vs 94.4±16.3 mg/24hr respectively) p‐value=0.026. When examining renal immune cell infiltration, we observed a nonsignificant reduction in infiltration of total leukocytes in the drug treated rats when compared to vehicle treated rats (2.1±0.3 vs 3.3±0.6 X10^6 CD45+ cells/kidney p=0.141). The drop was primarily due to a decrease in CD11b/c+ cells of the monocyte/macrophage lineage. These studies are the first to demonstrate an important role of the MCP‐1/CCR2 pathway in the development of hypertension, renal damage and renal immune cell infiltration in the Dahl‐SS rat. These studies prompt further investigation into this mechanism and the specific subsets of immune cells targeted. Follow‐up studies are ongoing to assess effect of blocking this pathway only in the kidneys to determine renal specific effects.Support or Funding InformationSupported by HL137748, HL116264 and AHA 15SFRN2391002.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.