Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis

Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type l-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both l-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by l-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both l-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type l-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, l-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.

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The Role of the Glucocorticoid Receptor in Mineralocorticoid/Salt-Mediated Cardiac Fibrosis

Endocrinology ◽

10.1210/en.2006-0658 ◽

2006 ◽

Vol 147 (12) ◽

pp. 5901-5906 ◽

Cited By ~ 30

Author(s):

Amanda J. Rickard ◽

John W. Funder ◽

Peter J. Fuller ◽

Morag J. Young

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Systolic Blood Pressure ◽

Glucocorticoid Receptors ◽

Cardiac Fibrosis ◽

Vascular Inflammation ◽

Vascular Wall ◽

Mrna Levels ◽

Markers Of Oxidative Stress

The pathophysiological consequences of excess mineralocorticoid for salt status include hypertension, vascular inflammation, and cardiac fibrosis. Mineralocorticoid receptor (MR) blockade can both prevent and reverse established inflammation and fibrosis due to exogenous mineralocorticoids or endogenous glucocorticoid activation of the MR. Glucocorticoids also exert potent antiinflammatory effects via glucocorticoid receptors (GR) in the vascular wall. We propose that GR signaling may ameliorate mineralocorticoid/salt-induced vascular inflammation and fibrosis in the mineralocorticoid/salt model. In the present study, the role of GR in the mineralocorticoid/salt model was explored in uninephrectomized rats that were maintained on 0.9% saline solution to drink and treated as follows: control (CON), no further treatment; deoxycorticosterone (DOC; 20 mg/wk) for 4 wk (DOC4); DOC for 8 wk (DOC8); DOC for 8 wk plus the GR antagonist RU486 (2 mg/d) wk 5–8 (DOC8/RU486); and DOC for 8 wk plus RU486 and the MR antagonist eplerenone (EPL; 50 mg/kg·d) for wk 5–8 (DOC8/RU486+EPL). DOC treatment significantly increased systolic blood pressure, cardiac fibrosis, inflammation (ED-1-positive macrophages and osteopontin), and mRNA for markers of oxidative stress (p22phox, gp91phox, and NAD(P)H-4). GR blockade reduced the DOC-mediated increase in systolic blood pressure and the number of infiltrating ED-1-positive macrophages but had no effect on fibrosis, oxidative stress, or osteopontin mRNA levels. EPL reversed DOC-induced pathology in the absence or presence of GR blockade. Thus, blocking agonist activity at the GR neither enhances nor attenuates the fibrotic response, although it may modulate systolic blood pressure and macrophage recruitment in the mineralocorticoid/salt model.

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Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart

Clinical Science ◽

10.1042/cs20080247 ◽

2009 ◽

Vol 116 (9) ◽

pp. 731-739 ◽

Cited By ~ 30

Author(s):

Peter Wilson ◽

James Morgan ◽

John W. Funder ◽

Peter J. Fuller ◽

Morag J. Young

Keyword(s):

Oxidative Stress ◽

Mrna Expression ◽

Mineralocorticoid Receptor ◽

Time Course ◽

Cardiac Fibrosis ◽

Inflammatory Responses ◽

Receptor Activation ◽

Mrna Levels ◽

Tissue Remodelling ◽

Perivascular Inflammation

Coronary, vascular and perivascular inflammation in rats following MR (mineralocorticoid receptor) activation plus salt are well-characterized precursors for the appearance of cardiac fibrosis. Endogenous corticosterone, in the presence of the 11βHSD2 (11β hydroxysteroid dehydrogenase type 2) inhibitor CBX (carbenoxolone) plus salt, produces similar inflammatory responses and tissue remodelling via activation of MR. MR-mediated oxidative stress has previously been suggested to account for these responses. In the present study we thus postulated that when 11βHSD2 is inhibited, endogenous corticosterone bound to unprotected MR in the vessel wall may similarly increase early biomarkers of oxidative stress. Uninephrectomized rats received either DOC (deoxycorticosterone), CBX or CBX plus the MR antagonist EPL (eplerenone) together with 0.9% saline to drink for 4, 8 or 16 days. Uninephrectomized rats maintained on 0.9% saline for 8 days served as controls. After 4 days, both DOC and CBX increased both macrophage infiltration and mRNA expression of the p22phox subunit of NADPH oxidase, whereas CBX, but not DOC, increased expression of the NOX2 (gp91phox) subunit. eNOS [endothelial NOS (NO synthase)] mRNA expression significantly decreased from 4 days for both treatments, and iNOS (inducible NOS) mRNA levels increased after 16 days of DOC or CBX; co-administration of EPL inhibited all responses to CBX. The responses characterized over this time course occurred before measurable increases in cardiac hypertrophy or fibrosis. The findings of the present study support the hypothesis that endogenous corticosterone in the presence of CBX can activate vascular MR to produce both inflammatory and oxidative tissue responses well before the onset of fibrosis, that the two MR ligands induce differential but overlapping patterns of gene expression, and that elevation of NOX2 subunit levels does not appear necessary for full expression of MR-mediated inflammatory and fibrogenic responses.

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Study of the mechanisms of aldosterone prothrombotic effect in rats

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320310397405 ◽

2011 ◽

Vol 12 (4) ◽

pp. 430-439 ◽

Cited By ~ 27

Author(s):

Anna Gromotowicz ◽

Janusz Szemraj ◽

Adrian Stankiewicz ◽

Agnieszka Zakrzeska ◽

Maria Mantur ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nadph Oxidase ◽

Venous Thrombosis ◽

Platelet Adhesion ◽

Thrombus Formation ◽

Mrna Levels ◽

Stress Dependent ◽

And Oxidative Stress ◽

Pai 1

Introduction: We investigated the role of primary haemostasis, fibrinolysis, nitric oxide (NO) and oxidative stress as well as mineralocorticoid receptors (MR) in acute aldosterone prothrombotic action. Materials and methods: Venous thrombosis was induced by stasis in Wistar rats. Aldosterone (ALDO; 10, 30, 100 µg/kg/h) was infused for 1 h. Eplerenone (EPL; 100 mg/kg, p.o.), a selective MR antagonist, was administered before ALDO infusion. Bleeding time (BT) and platelet adhesion to collagen were evaluated. The expression of nitric oxide synthase (NOS), NADPH oxidase, superoxide dismutase (SOD) and plasminogen activator inhibitor (PAI-1) was measured. NO, malonyl dialdehyde (MDA) and hydrogen peroxide (H2O2) plasma levels were assayed. Results: Significant enhancement of venous thrombosis was observed after ALDO infusion. ALDO shortened BT and increased platelet adhesion. Marked increases were observed in PAI-1, NADPH oxidase and SOD mRNA levels. MDA and H2O2 levels were augmented in ALDO-treated groups, and NOS expression and NO level were decreased. EPL reduced ALDO effects on thrombus formation, primary haemostasis, PAI-1 expression and MDA level. Conclusion: Short-term ALDO infusion enhances experimental venous thrombosis in the mechanism involving primary haemostasis, fibrinolysis, NO and oxidative stress-dependent pathways. The MR antagonist only partially diminished the ALDO effects, suggesting the involvement of additional mechanisms.

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Rosiglitazone Decreases Blood Pressure in Female Dahl Rats: Role of Nitric Oxide and Oxidative Stress

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.941.16 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Julio C. Sartori‐Valinotti ◽

Michael J. Ryan ◽

Huimin Zhang ◽

Jane F. Reckelhoff

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

And Oxidative Stress

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Endothelial dysfunction and oxidative stress in polycystic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00327.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. F1198-F1206 ◽

Cited By ~ 45

Author(s):

Jelena Klawitter ◽

Berenice Y. Reed-Gitomer ◽

Kim McFann ◽

Alexander Pennington ◽

Jost Klawitter ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Endothelial Dysfunction ◽

Systolic Blood Pressure ◽

The Body ◽

Mass Spectrometry Analysis ◽

Oxidative Stress Marker ◽

Kidney Volume ◽

Healthy Controls ◽

And Oxidative Stress

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min−1·1.73 m−2] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25–60 ml·min−1·1.73 m−2). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min−1·1.73 m−2 showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [ S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD2, and PGE2, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD2 and PGF2α were associated with reduced eGFR, whereas 8-isoprostane and again PGF2α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

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ACE2 and the Homolog Collectrin in the Modulation of Nitric Oxide and Oxidative Stress in Blood Pressure Homeostasis and Vascular Injury

Antioxidants and Redox Signaling ◽

10.1089/ars.2016.6950 ◽

2017 ◽

Vol 26 (12) ◽

pp. 645-659 ◽

Cited By ~ 7

Author(s):

Guang Yang ◽

Pei-Lun Chu ◽

Lars C. Rump ◽

Thu H. Le ◽

Johannes Stegbauer

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

Vascular Injury ◽

Blood Pressure Homeostasis ◽

And Oxidative Stress

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Adenosine A1-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00268.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. R1669-R1681 ◽

Cited By ~ 20

Author(s):

Xiang Gao ◽

Andreas Patzak ◽

Mauricio Sendeski ◽

Peter G. Scheffer ◽

Tom Teerlink ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

Tubuloglomerular Feedback ◽

Oxidative Stress Marker ◽

No Production ◽

Ang Ii ◽

Simultaneous Treatment ◽

Blood Pressure Responses ◽

And Oxidative Stress

Adenosine mediates tubuloglomerular feedback responses via activation of A1-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A1-receptor knockout (A1−/−) and wild-type (A1+/+) mice we investigated the hypothesis that A1-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) or ANG II treatment. The hypertensive responses to l-NAME and ANG II were clearly attenuated in A1−/− mice. Arteriolar contractions to l-NAME (10−4 mol/l; 15 min) and cumulative ANG II application (10−12 to 10−6 mol/l) were lower in A1−/− mice. Simultaneous treatment with tempol (10−4 mol/l; 15 min) attenuated arteriolar responses in A1+/+ but not in A1−/− mice, suggesting differences in ROS formation. Chronic treatment with l-NAME or ANG II did not alter arteriolar responses in A1−/− mice, but enhanced maximal contractions in A1+/+ mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A1+/+ mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A1-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A1-receptor signaling blunts l-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.

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Increase in Nitric Oxide and Reductions in Blood Pressure, Protein Kinase C β II and Oxidative Stress by L-Carnitine: A Study in the Fructose-Fed Hypertensive Rat

Clinical and Experimental Hypertension ◽

10.1080/10641960701743998 ◽

2007 ◽

Vol 29 (8) ◽

pp. 517-530 ◽

Cited By ~ 28

Author(s):

P. Rajasekar ◽

N. Palanisamy ◽

C.V. Anuradha

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

Protein Kinase C ◽

Protein Kinase ◽

Kinase C ◽

Hypertensive Rat ◽

And Oxidative Stress

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Administration of Telmisartan Reduced Systolic Blood Pressure and Oxidative Stress Probably Through the Activation of PI3K/Akt/eNOS Pathway and NO Release in Spontaneously Hypertensive Rats

Physiological Research ◽

10.33549/physiolres.932433 ◽

2013 ◽

pp. 351-359 ◽

Cited By ~ 15

Author(s):

L. XU ◽

Y. LIU

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

Angiotensin Ii Receptor ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

No Release ◽

And Oxidative Stress

We investigated the effects of telmisartan, the blocker of angiotensin II receptor 1, on the regulation of systolic blood pressure (SBP) and oxidative stress through endothelial nitric oxide (NO) release in spontaneously hypertensive rats (SHRs). SHRs randomly received placebo, oral feeding of telmisartan (5 mg/kg or 10 mg/kg) every day and Wistar-Kyoto rats (WKYs) served as normotensive control. The SBP of rat was measured before and weekly thereafter. After a total of 8-week treatment, rats were killed for experimental measurements. Parameters that subject to measurements in isolated aorta endothelial cells include: NO concentration, protein expression levels of angiotensin II receptor 1, nitrotyrosine, 8-isoprostane, SOD, PI3K, Akt, AMPK and eNOS. In addition, L-NMMA, a general inhibitor of nitric oxide synthase, was also applied to test the inhibition of NO concentration. We found that SBPs were significantly lower in telmisartan therapy group than in placebo treated hypertensive rats and WKYs (p<0.05). The NO concentration was significantly higher in telmisartan-treated group with increased activity of the PI3K/Akt pathway and activated eNOS signaling. Blockade of Akt activity reversed such effects. Activation of AMPK also contributed to the phosphorylation of eNOS. L-NMMA treatment reduced less NO concentration in SHR rats than the telmisartan co-treated groups. Oxidative stress in SHRs was also attenuated by telmisartan administration, shown by reduced formation of nitrotyrosine, 8-isoprostane, and recovered SOD protein level. Telmisartan enhanced NO release by activating the PI3K/Akt system, AMPK phosphorylation and eNOS expression, which attenuated the blood pressure and oxidative stress in SHRs.

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