Table 1.

Lineage-specific MR knockout effects in animal models

Author, model	Cell-specific effects of MRKO	Phenotype
Myeloid MRKO Shen et al. [44], 2016 Uninephrectomized DOCA-salt	↑ Cardiac M2 macrophage markers PPARy, PDK4, MRC2, CXCL9, ↓ TNFα, MMP12 expression	↓ Cardiac fibrosis
Rickard et al. [93], 2009 Uninephrectomized DOCA-salt	↓ Cardiac macrophage infiltration, collagen, PAI-1, NADPH oxidase	↓ Cardiac fibrosis and hypertrophy
Usher et al. [94], 2010 Uninephrectomized L-NAME/salt treated	↓ Peritoneal macrophage TNFα, rantes, IL12, ILIβ, MCP2 expression ↑ Arg1, IL10, Ym1, FIZZ1, F13a1, CCL-17, CCL-7 expression ↓ Cardiac macrophage infiltration ↓ ANP, BNP, collagen III, TGFβ, PAI-1	↓ L-NAME/AngII-induced cardiac interstitial fibrosis, aortic fibrosis, and thickening
Bienvenu et al. [50], 2012 Uninephrectomized L-NAME/salt treated	↓ CTGF, collagen III, TNFα expression MRKO made no difference in macrophage infiltration	↓ Cardiac and large vessel fibrosis
Li et al. [49], 2014 AAC mice	↓ Cardiomyocyte hypertrophy, ANP, βMHC, collagen I/III, CTGF, fibronectin 1, TGFβ1, and TGFβ2 expression, aortic collagen I/III, CTGF staining ↓ Cardiac Nox2, Nox4, p40, p47 ↑ MnSOD expression Rescued AAC-induced cardiac β-oxidation (Acox1, Acadm, and Acadvl) and oxidative phosphorylation (Sdhb, Cox4i1, Atp5j), ↑ Cardiac PPARα and PGCla expression ↓ Cardiac macrophage M1 markers F4/80 and CD68, M1 cytokines TNFα, MIPIβ, COX2, MCP1, and IL6 staining ↓ Cardiac and aortic macrophage infiltration	⇊ Cardiac fibrosis and hypertrophy ↓ Aortic fibrosis
Shen et al. [45], 2017 LDLR null mice	↓ Plaque necrotic core area, macrophage accumulation, in vitro foam cell formation ↑ Plaque collagen area	↓ Atherosclerotic lesion area (aorta)
Zhang et al. [95], 2017 Lepob/ob	↑ ERα and ESR1 gene expression ↑ HGF expression ↑ Hepatocyte Met signaling ↑ Insulin sensitivity ↓ Hepatic triglyceride storage and lipogenesis genes - SCD1, Ly6d, and Cidea	↑ Glucose homeostasis ↓ Hepatic steatosis
Sun et al. [47], 2016 Femoral artery wire injury in MRKO mice	↓ Injury-induced vascular macrophage infiltration and proliferation, smooth muscle proliferation ↓ Injury-induced vascular AP-1, NFκB, SGK1 signaling, IL6, IL1β, ICAM1, MIPlα, MIPIβ, MIP2α, NOS2, MMP9, CXCL1, MCP1, CCR2, CCR4, osteopontin	↓ Injury-induced intimai hyperplasia and fibrosis
Frieler et al. [96], 2011 Focal cerebral ischemia	↓ Infarct-induced myeloid TNFα, IL1β, MCP1, MIP1α, and IL6 ↑ Myeloid Arg1 and Ym1	65% reduction in infarct volume ↓ Infarct-induced microglial activation in the ischemic core
Endothelial MRKO Rickard et al. [97], 2014 Uninephrectomized DOCA-salt or aldosterone Duration: 8 weeks	↓ Cardiac CCR5 expression at 8 days ↓ Cardiac CTGF expression at 8 weeks ↓ DOCA-salt-induced cardiac macrophage infiltration and fibrosis at 8 weeks Eplerenone inhibited aldosterone-induced ICAM1 and CTGF expression in HUVEC cells	↓ Aldo-induced endothelial dysfunction in aorta but not mesenteric resistance vessels, as measured by Ach-induced relaxation
Schäfer et al. [98], 2013 ND or a HFD and Aldosterone infused mice	↓ Diet-induced endothelial dysfunction ↓ Aldo-induced COX1 expression Indomethacin reduced aldosterone infusion-induced endothelial dysfunction to same extent as MRKO	EC MR−/− had no effect on WAT inflammatory state or glucose tolerance of obese or aldo infused mice EC MR−/− prevented HFD and aldo infusion-induced endothelial dysfunction
Jia et al. [99], 2015 Control vs. high fat and carbohydrate diet (western; WD)	↓ WD-induced cardiomyocyte stiffness (by atomic force microscopy), cardiac TGFβ1, and phospho-Smad2/3, collagen I, CTGF, and fibronectin immunostaining ↓ WD-induced cardiac 3-nitrotyrosine staining ↓ WD-induced cardiac pS6K, pIRS1, pERK1/2, M1 markers MCP1, IL17, CD11b immunostaining CD206 and IL1O immunostaining	↓ WD-induced diastolic dysfunction (evaluated by relaxation time and Doppler), cardiac interstitial fibrosis and hypertrophy
Jia et al. [100], 2016 Chow or western diet for 16 weeks	KO attenuated WD-induced aortic endothelial decreases in p-AKT and p-eNOS ↑ Mesenteric artery flow-induced vasodilation ↓ WD-induced aortic endothelial 3-nitrotyrosine immunostaining ↓ WD-induced aortic pERK immunoblot, and osteopontin, FGF23 immunostaining ↑ M2: M1 marker ratios (↓MI markers CD86, and CD11c; ↑M2 markers CD206 and IL10) ↓ WD-induced aortic ENaC expression	↓WD-induced aortic stiffness (evaluated by pulse wave velocity and atomic force microscopy), aortic endothelial dysfunction, aortic medial thickening, and fibrosis
VSMC MRKO McCurley et al. [101], 2012 Tamoxifen-induced MRf/f/SMA-Cre-ERT2+ and tamoxifen-induced MRf/f/SMA-Cre-ERT2- littermate controls with no alterations in feeding or growth	↓ Mesenteric artery L-type Ca-channel Cav1.2 expression ↓ AngII-induced ROS production	Age-dependent decrease in systolic blood pressure, becoming significant at 7 months of age ↓ Age-related cardiac hypertrophy ↓ Mesenteric artery myogenic tone ↓ AngII-induced pressor response
Amador et al. [102], 2016 CsA-induced nephrotoxicity model	↓ CsA-induced NGAL expression, marker of tubular injury ↓ CsA-induced pMLCKMLCK, pMLC2:MLC2 ratios, markers of SMC contractility ↓ CsA-induced L-type Ca-channel Cav1.2 activation	SMC MR inactivation but not EC MR inactivation prevents cyclosporine-induced uremia, creatininemia, and tubular vacuolization ↓ Renal vasculature Angll and KCl-induced contractile response
Galmiche et al. [103], 2014 NAS hypertension model	↓ NAS-induced carotid a5-integrin expression	↓ NAS-induced carotid stiffness No changes in vascular structure
Pruthi et al. [104], 2014 Wire-induced carotid injury model and aldosterone enhanced vascular fibrosis model	↓ Wire injury-induced VEGFR1 expression ↓ Aldo-induced P1GF expression	Prevented aldosterone-induced 79% increase in SMC proliferation post wire injury Prevents aldosterone-induced vascular fibrosis post wire injury llnjury-induced medial hypertrophy
Cardiomyocyte MRKO Rickard et al. [105], 2012 Uninephrectomized DOCA-salt	↑ Cardiac MMP9: TIMP-1 mRNA expression ratio ↓ DOCA-salt-induced cardiac PAI-1, CCR5, Nox2, p22Phox, TGFβ1, VEGF, VEGFR2, MCP1, CD14, CD81 expression ↓ DOCA-salt-induced cardiac macrophage infiltration, CD45+ leukocytes, CD8+ T cells	↓ DOCA-salt-induced cardiac fibrosis, positive inotropic state as assessed by Langendorff apparatus measured pressure and contraction/relaxation times
Fraccarollo et al. [106], 2011 Cardiomyocytes LCA ligation model	↓ MI-induced collagen, ACE, CTGF, fibronectin, periostin, vimentin expression ↓ MI-induced NADPH oxidase subunits Nox2, Nox4, and chronic Mi-induced mitochondrial ROS production ↑ Acute MI-induced NF-κB activation ↓ IκBα and cardiomyocyte apoptosis (TUNEL assay) ↑ Neutrophil and macrophage infiltration 1 day post-acute MI	↓ Post-MI rightward shift in PV loop, infarct area expansion, Post-MI cardiac hypertrophy, and attenuatation of progressive LV dilation ↑ Scar thickness, post-MI ejection fraction, post-MI capillary density at 1 day post-acute MI
Lother et al. [107], 2011 Cardiomyocytes Chronic left ventricular pressure overload by TAC model	↑ TAC-induced ANP, βMHC gene expression ↑ ERK1/2 phosphorylation and ↓ TAC-induced increase in SGK1 mRNA expression	Prevented TAC-induced ventricular dilation Prevented TAC-induced LV wall stress Prevented TAC-induced decline in ejection fraction TAC led to cardiac fibrosis and was unaffected by MRKO
CD4+ T cell MRKO Li et al. [108], 2017 T cells AAC mouse model	↓ Cardiomyocyte hypertrophy ↓ Cardiac CD11b+Ly6C+, CD11b+Ly6C−, Ly6Chi, macrophage, neutrophil, CD4+ & CD8+ T cell, CD4+CD69+, CD8+CD69+, CD4+CD44hiCD62low, CD8+CD44hiCD62low T cell infiltration, ANP, βMHC, collagen I/III, CTGF, TGFβ1 expression ↓ Anti-CD3 stimulated IL2, IFNγ, and IL6	↓ AAC-induced cardiac hypertrophy, fibrosis, LV dilation Improved ejection fraction
Sun et al. [66], 2017 T cells Angll-induced hypertensive mouse model	↓ AngII-induced renal CD11b macrophage, CD4+ and CD8+, CD4+IFNγ+, CD8+IFNγ+ T cell infiltration, ↓ NGAL, osteopontin, MCP1, and VCAM1 1 AngII-induced aortic macrophage infiltration, CD4+ and CD8+, CD4+IFNγ+, and CD8+IFNγ+ T cell infiltration ↓ RANTES & MCP1	↓ AngII-induced hypertension, glomerular hypertrophy, renal fibrosis, albuminuria aortic fibrosis, endothelial dysfunction

AAC, abdominal aortic constriction; Ach, acetylcholine; AngII, angiotensin II; ACE, angiotensin I converting enzyme (peptidyl-dipeptidase A) 1; Aldo, aldosterone; ANP, natriuretic peptide precursor type A; Arg1, arginase 1; BNP, natriuretic peptide precursor type B/brain natriuretic peptide; Cav1.2, calcium channel, voltage-dependent, L type, alpha 1C subunit; CCL, chemokine (C-C motif) ligand; Cidea, cell death-inducing DNA fragmentation factor, alpha subunit-like effector A; COX, cytochrome c oxidase; CTGF, connective tissue growth factor; CsA, cyclosporine A; DOCA, deoxycorticosterone acetate; CXCL, chemokine (C-X-C motif) ligand; EC, endothelial cell; ENaC, endothelial sodium channel; ER, estrogen receptor; ERK, extracellular regulated MAP kinase; F13a1, coagulation factor XIII, A1 subunit; ESR1, estrogen receptor 1; FIZZ1, found in inflammatory zone 1; HFD, high fat diet; HGF, hepatocyte growth factor; IFNγ, interferon gamma; IL, interleukin; L-NAME, L-NG-nitroarginine methyl ester; MMP, matrix metalloproteinase; MnSOD, manganese superoxide dismutase; MCP1, chemokine (C-C motif) ligand 2; M2, macrophage phenotype 2 – alternatively activated; βMHC, beta myosin heavy chain; MIP1β, chemokine (C-C motif) ligand 4 (CCL4); NGAL, lipocalin 2; MRC2, mannose receptor, C type 2; NAS, Nephrectomy–aldosterone–salt; ND, normal chow diet; Nox2, NADPH oxidase 2/cytochrome b-245, beta polypeptide; NOX4, NADPH oxidase 4; PAI-1, plasminogen activator inhibitor-1; RANTES, chemokine (C-C motif) ligand 5; SGK1, serum/glucocorticoid regulated kinase 1; TAC, transverse aortic constriction; ROS, reactive oxygen species; SCD1, stearoyl-Coenzyme A desaturase 1; TNF, tumor necrosis factor; TGF, transforming growth factor; TIMP1, tissue inhibitor of metalloproteinase 1; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VEGFR, endothelial growth factor receptor; VSMC, vascular smooth muscle cell; WD, western diet.