Premium
CCL2 Mediates Early Renal Leukocyte Infiltration During Salt‐Sensitive Hypertension
Author(s) -
Alsheikh Ammar J.,
Dasinger John Henry,
Abais-Battad Justine M.,
Fehrenbach Daniel J.,
Yang Chun,
Cowley Allen W.,
Mattson David L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02986
Subject(s) - ccr2 , medicine , chemokine , kidney , infiltration (hvac) , pathophysiology of hypertension , ccl2 , essential hypertension , antagonist , pharmacology , endocrinology , receptor , immunology , chemokine receptor , blood pressure , physics , thermodynamics
Background Hypertension is reported to be the largest independent risk factor for disease burden globally. Despite the prevalence and burden of hypertension on human health, the mechanisms leading to the development of hypertension in most individuals remain unknown. Both human and animal experimental evidence indicate that immune mechanisms may play a key role in the development of hypertension and associated end‐organ damage. Studies examining mechanisms of Dahl Salt‐Sensitive (SS) hypertension have implicated the infiltration of leukocytes into the kidneys as a key contributor to the hypertension and renal damage. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. Aim The aim of the present set of studies was to use a unique unbiased discovery‐based approach to nominate signaling pathways which was followed by functional testing of the role of the identified pathways in renal leukocyte infiltration. Methods and Results We analyzed a kidney RNA‐seq dataset from SS rats fed either a Low Salt (LS‐0.4% NaCl) or a High Salt (HS‐4.0% NaCl) diet. From this analysis, the chemokine (C‐C motif) ligand 2 (CCL2) and receptor CCR2 were nominated as a potential pathway modifying renal leukocyte infiltration. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS102895 at 5mg/kg/day in DMSO) or DMSO Vehicle for 3 days (n=13–15/group) or 21 days (n=9–11/group) by intraperitoneal injections to male SS rats during the HS challenge. A variety of parameters were measured throughout the study including blood pressure (measured continuously using radio‐telemetry), circulating leukocytes and renal leukocyte infiltration (by flow cytometry) and renal damage (assessed histologically and using urinary injury markers), body weight, food intake and electrolyte excretion. Results demonstrate that RS201895 treatment, compared to vehicle‐treated rats ameliorated renal damage (urinary albumin excretion; 43.4±5.1 vs 114.7±15.2 mg/day, P<001) and hypertension (144.3±2.2 vs 158.9±4.8 mmHg, P<0.001) after 21 days of HS diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the HS diet (1.4±0.1 vs 1.9±0.2 ×10 6 CD45+ cells/kidney, P=0.034) in drug‐treated rats. A unique adaptation of an in vitro chemotaxis assay validated the ability of RS102895 to block leukocyte chemotaxis towards CCL2 at in vivo concentrations. Conclusion/Significance The results demonstrate that increased CCL2 in SS kidney is important in early recruitment of leukocytes and blockade of this recruitment by administering RS102895, which subsequently ameliorated the renal damage and hypertension. These results provide a unique understanding to an important disease process that has potential therapeutic implications. Support or Funding Information Supported by HL137748, HL116264.