title: Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure.
abstract: Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR(flox/flox)/LysM(Cre/-) mice). Male mice from each genotype (MR(flox/flox) or wild-type and MR(flox/flox)/LysM(Cre/-) mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR(flox/flox)/LysM(Cre/-) mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR(flox/flox)/LysM(Cre/-) mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR(flox/flox)/LysM(Cre/-) mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton 3168, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Rickard
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.forename: Greg
authors.initials: G
authors.lastname: Tesch
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005355:Fibrosis / Q000209:etiology; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009392:Nephrectomy; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D003094:Collagen; D003900:Desoxycorticosterone; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse