Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End- organ Damage

Background Aldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown. Methods We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5+/+) and CCR5 knockout (CCR5−/−) mice treated with aldosterone (600 µg/kg/day for 14 days) while receiving 1% saline to drink. Results Here, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5+/+ mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NFκB activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NFκB, or with Maraviroc treatment. Conclusions Our data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess. ### Competing Interest Statement The authors have declared no competing interest. * ACh : 4,5-Diaminofluorescein Diacetate (DAF-2 DA) Acetylcholine CCL5 : Chemokine (C-C motif) Ligand 5 DBP : Diastolic Blood Pressure DMEM : Dulbecco’s Modified Eagle’s Medium ELISA : Enzyme-Linked Immunosorbent Assay LTA : Lotus Tetragonolobus Lectin MAP : Mean arterial pressure MR : Mineralocorticoid Receptors NFκB : Nuclear Factor Kappa B PBS-T : PBS containing 0.1% Tween-20 PE : Phenylephrine PBS : Phosphate-Buffered Saline ROS : Reactive Oxygen Species RANTES : Regulated on Activation Normal T Cell Expressed and Secreted SNP : Sodium Nitroprusside SBP : Systolic Blood Pressure T-Reg : T-Regulatory Cells VSMC : Vascular Smooth Muscle Cells