Abstract 096: Progesterone Upregulates Endothelial Mineralocorticoid Receptor Expression Which Predisposes Female Mice to Obesity-Induced Endothelial Dysfunction

Abstract Background Recent evidence by our laboratory demonstrates that women and female mice endogenously express higher endothelial mineralocorticoid receptor (ECMR) than males. Mounting clinical evidence also indicates that aldosterone production is higher in pathological conditions in females compared to males. However, the role for increased activation of ECMR by aldosterone in the absence of a comorbid condition is yet to be explored. The current study hypothesized that increased ECMR activation induced by elevated aldosterone production predisposes healthy female mice to endothelial dysfunction. Method Vascular reactivity was assessed in aortic rings from wild-type (WT) and ECMR KO (KO) mice fed either a normal salt (NSD, 0.4% NaCl) or sodium-restricted diet (SRD, 0.05% NaCl) for 28 days. Results SRD elevated plasma aldosterone levels as well as adrenal CYP11B2 and angiotensin II type 1 receptor (AT1R) expressions in female, but not male, WT mice. In baseline conditions (NSD), endothelial function, assessed by vascular relaxation to acetylcholine, was higher while vascular contractility to phenylephrine, serotonin, and KCl lower in female than male WT mice. SRD impaired endothelial function and increased vascular contractility in female, but not male, WT mice effectively ablating the baseline sex differences. NOS inhibition with LNAME ablated endothelial relaxation to a higher extent in male than female mice on NSD and ablated differences in acetylcholine relaxation responses between NSD- and SRD-fed females, indicating a role for NO in SRD-mediated endothelial function. In association, SRD significantly reduced vascular NOX4 expression in female, but not male, mice. Lastly, selective deletion of ECMR protected female mice from SRD-mediated endothelial dysfunction and increased vascular contractility. Conclusion Collectively, these data indicate that female mice develop aldosterone-induced endothelial dysfunction via endothelial MR-mediated reductions in NO bioavailability. In addition, these data support a role for ECMR to promote vascular contractility in female mice in response to sodium restriction.

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Mineralocorticoid Receptor in Myeloid Cells Mediates Angiotensin II-Induced Vascular Dysfunction in Female Mice

Frontiers in Physiology ◽

10.3389/fphys.2021.588358 ◽

2021 ◽

Vol 12 ◽

Author(s):

Camila Manrique-Acevedo ◽

Jaume Padilla ◽

Huma Naz ◽

Makenzie L. Woodford ◽

Thaysa Ghiarone ◽

...

Keyword(s):

Adipose Tissue ◽

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Mineralocorticoid Receptor ◽

Vascular Dysfunction ◽

Macrophage Polarization ◽

Myeloid Cells ◽

Ang Ii ◽

Female Mice

Enhanced mineralocorticoid receptor (MR) signaling is critical to the development of endothelial dysfunction and arterial stiffening. However, there is a lack of knowledge about the role of MR-induced adipose tissue inflammation in the genesis of vascular dysfunction in women. In this study, we hypothesize that MR activation in myeloid cells contributes to angiotensin II (Ang II)-induced aortic stiffening and endothelial dysfunction in females via increased pro-inflammatory (M1) macrophage polarization. Female mice lacking MR in myeloid cells (MyMRKO) were infused with Ang II (500 ng/kg/min) for 4 weeks. This was followed by determinations of aortic stiffness and vasomotor responses, as well as measurements of markers of inflammation and macrophage infiltration/polarization in different adipose tissue compartments. MyMRKO mice were protected against Ang II-induced aortic endothelial stiffening, as assessed via atomic force microscopy in aortic explants, and vasorelaxation dysfunction, as measured by aortic wire myography. In alignment, MyMRKO mice were protected against Ang II-induced macrophage infiltration and M1 polarization in visceral adipose tissue (VAT) and thoracic perivascular adipose tissue (tPVAT). Collectively, this study demonstrates a critical role of MR activation in myeloid cells in the pathogenesis of vascular dysfunction in females associated with pro-inflammatory macrophage polarization in VAT and tPVAT. Our data have potential clinical implications for the prevention and management of cardiovascular disease in women, who are disproportionally at higher risk for poor outcomes.

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MicroRNAs regulate aldosterone signaling by post-transcriptional control of mineralocorticoid receptor expression

Endocrine Abstracts ◽

10.1530/endoabs.63.p1018 ◽

2019 ◽

Author(s):

Thi-An Vu ◽

Ingrid Lema ◽

Jerome Bouligand ◽

Laetitia Martinerie ◽

Marc Lombes ◽

...

Keyword(s):

Mineralocorticoid Receptor ◽

Transcriptional Control ◽

Receptor Expression

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Faculty Opinions recommendation of Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027243.326691 ◽

2005 ◽

Author(s):

Elise Gomez-Sanchez

Keyword(s):

Mineralocorticoid Receptor ◽

Receptor Expression

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Faculty Opinions recommendation of Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162925.623552 ◽

2009 ◽

Author(s):

Bellamkonda Kishore

Keyword(s):

Mineralocorticoid Receptor ◽

Receptor Expression

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Mineralocorticoid receptor expression and increased survival following neuronal injury

European Journal of Neuroscience ◽

10.1046/j.1460-9568.2003.02587.x ◽

2003 ◽

Vol 17 (8) ◽

pp. 1549-1555 ◽

Cited By ~ 44

Author(s):

Malcolm R. Macleod ◽

Inga-Maj Johansson ◽

Ingegerd Söderström ◽

Maggie Lai ◽

Gunilla Gidö ◽

...

Keyword(s):

Mineralocorticoid Receptor ◽

Neuronal Injury ◽

Receptor Expression

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Regulation of Mineralocorticoid Receptor Expression during Neuronal Differentiation of Murine Embryonic Stem Cells

Endocrinology ◽

10.1210/en.2009-0753 ◽

2010 ◽

Vol 151 (5) ◽

pp. 2244-2254 ◽

Cited By ~ 19

Author(s):

Mathilde Munier ◽

Geri Meduri ◽

Say Viengchareun ◽

Philippe Leclerc ◽

Damien Le Menuet ◽

...

Keyword(s):

Neuronal Differentiation ◽

Mineralocorticoid Receptor ◽

Fluorescent Protein ◽

Morphological Changes ◽

Critical Role ◽

Embryonic Stem ◽

Embryoid Bodies ◽

Receptor Expression ◽

Neuronal Markers ◽

Mature Neurons

Mineralocorticoid receptor (MR) plays a critical role in brain function. However, the regulatory mechanisms controlling neuronal MR expression that constitutes a key element of the hormonal response are currently unknown. Two alternative P1 and P2 promoters drive human MR gene transcription. To examine promoter activities and their regulation during neuronal differentiation and in mature neurons, we generated stably transfected recombinant murine embryonic stem cell (ES) lines, namely P1-GFP and P2-GFP, in which each promoter drove the expression of the reporter gene green fluorescent protein (GFP). An optimized protocol, using embryoid bodies and retinoic acid, permitted us to obtain a reproducible neuronal differentiation as revealed by the decrease in phosphatase alkaline activity, the concomitant appearance of morphological changes (neurites), and the increase in the expression of neuronal markers (nestin, β-tubulin III, and microtubule-associated protein-2) as demonstrated by immunocytochemistry and quantitative PCR. Using these cell-based models, we showed that MR expression increased by 5-fold during neuronal differentiation, MR being preferentially if not exclusively expressed in mature neurons. Although the P2 promoter was always weaker than the P1 promoter during neuronal differentiation, their activities increased by 7- and 5-fold, respectively, and correlated with MR expression. Finally, although progesterone and dexamethasone were ineffective, aldosterone stimulated both P1 and P2 activity and MR expression, an effect that was abrogated by knockdown of MR by small interfering RNA. In conclusion, we provide evidence for a tight transcriptional control of MR expression during neuronal differentiation. Given the neuroprotective and antiapoptotic role proposed for MR, the neuronal differentiation of ES cell lines opens potential therapeutic perspectives in neurological and psychiatric diseases.

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Abstract 112: Myeloid Mineralocorticoid Receptor Controls Inflammatory and Fibrotic Responses After Renal Ischemic Injury via Macrophage Interleukin-4 Receptor

Hypertension ◽

10.1161/hyp.70.suppl_1.112 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Jonatan Barrera-Chimal ◽

Sebastian M Lechner ◽

Soumaya E Moghrabi ◽

Peter Kolkhof ◽

Frédéric Jaisser

Keyword(s):

Mineralocorticoid Receptor ◽

De Novo ◽

Interstitial Fibrosis ◽

Macrophage Polarization ◽

Peritoneal Macrophages ◽

Renal Ischemia ◽

Receptor Expression ◽

Interleukin 4 ◽

Mrna Levels ◽

Kidney Fibrosis

Introduction: Patients who survive an episode of acute kidney injury (AKI) are at high risk of de novo chronic kidney disease (CKD) development. Pharmacological mineralocorticoid receptor (MR) antagonism is useful to prevent CKD after a single episode of ischemic AKI in the rat. Objective: Test the involvement of myeloid MR in the development of kidney fibrosis after an ischemic AKI episode. Methods: We included 18 male C57/B6 mice that were divided in: sham, renal ischemia for 22.5 min and IR plus treatment with the non-steroidal MR antagonist finerenone (10 mg/kg) at -48, -24 and -1 h before IR. MR inactivation in myeloid cells (MR MyKO ) was achieved by crossing mice with the MR alleles flanked by loxP sites (MR f/f ) with mice expressing the Cre recombinase under the LysM promoter activity. In MR f/f and MR MyKO mice we induced renal IR of 22.5 min or sham surgery. The mice were followed-up during 4 weeks to test for AKI to CKD transition. In another set of mice, the macrophages were sorted from kidneys after 24 h of reperfusion and flow cytometry characterization or mRNA extraction was performed. Thyoglycolate elicited peritoneal macrophages were used for in vitro studies. Results: The progression of AKI to CKD after 4 weeks of renal ischemia in the untreated C57/B6 and MR f/f mice was characterized by a 50% increase in plasma creatinine, a 2-fold increase in the mRNA levels of TGF-β and fibronectin as well as by severe tubule-interstitial fibrosis. The mice that received finerenone or MR MyKO mice were protected against these alterations. Increased expression of M2-anti-inflamatory markers in kidney-isolated macrophages from finerenone-treated or MR MyKO mice was observed. The inflammatory population of Ly6C high macrophages was reduced by 50%. In peritoneal macrophages in culture, MR inhibition promoted increased IL-4 receptor expression and activation, facilitating macrophage polarization to an M2 phenotype. Conclusion: MR antagonism or myeloid MR deficiency facilitates macrophage polarization to a M2, anti-inflammatory phenotype after kidney IR, preventing maladaptive repair and chronic kidney fibrosis and dysfunction. MR inhibition acts through the modulation of IL-4 receptor signaling to facilitate macrophage phenotype switching.

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