Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure.
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.
Rickard
Amanda J
AJ
Prince Henry's Institute of Medical Research, Clayton 3168, Australia.
Morgan
James
J
Tesch
Greg
G
Funder
John W
JW
Fuller
Peter J
PJ
Young
Morag J
MJ
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
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