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International Journal of Molecular... Apr 2023Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical... (Review)
Review
Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of environmental perturbations and how their dysregulation compromises fluid homeostasis. In addition to these roles, the accumulation of data also provided unequivocal evidence that MR is involved in the pathophysiology of kidney diseases. Experimental studies delineated the diverse pathological consequences of MR overactivity and uncovered the multiple mechanisms that result in enhanced MR signaling. In parallel, clinical studies consistently demonstrated that MR blockade reduces albuminuria in patients with chronic kidney disease. Moreover, recent large-scale clinical studies using finerenone have provided evidence that the non-steroidal MR antagonist can retard the kidney disease progression in diabetic patients. In this article, we review experimental data demonstrating the critical importance of MR in mediating renal injury as well as clinical studies providing evidence on the renoprotective effects of MR blockade. We also discuss areas of future investigation, which include the benefit of non-steroidal MR antagonists in non-diabetic kidney disease patients, the identification of surrogate markers for MR signaling in the kidney, and the search for key downstream mediators whereby MR blockade confers renoprotection. Insights into these questions would help maximize the benefit of MR blockade in subjects with kidney diseases.
Topics: Humans; Albuminuria; Aldosterone; Kidney; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic
PubMed: 37175424
DOI: 10.3390/ijms24097719 -
Kidney International Oct 2023A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the...
A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut-kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension-sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype.
Topics: Humans; Aldosterone; Blood Pressure; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Sodium Chloride, Dietary
PubMed: 37454911
DOI: 10.1016/j.kint.2023.06.035 -
Redox Biology Dec 2023Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital...
Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins c-akt; Mineralocorticoid Receptor Antagonists; Phosphatidylinositol 3-Kinases; Signal Transduction; Diabetic Nephropathies; Mitochondria; Diabetes Mellitus
PubMed: 37924663
DOI: 10.1016/j.redox.2023.102946 -
The Journal of Clinical Investigation Jan 2024Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to...
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Topics: Rats; Humans; Animals; Mineralocorticoid Receptor Antagonists; Chromatin; Amiloride; Mineralocorticoids; Kidney; Hypertension; Kidney Diseases; Gene Expression Profiling
PubMed: 37906287
DOI: 10.1172/JCI157165 -
Circulation Research Feb 2020Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction...
Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress.
RATIONALE
Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.
OBJECTIVE
We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.
METHODS AND RESULTS
To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.
CONCLUSIONS
We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.
Topics: Angiotensin II; Animals; Desoxycorticosterone Acetate; Endothelium, Vascular; Essential Hypertension; Female; Heart; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria, Heart; Mitochondrial Proteins; Myocardium; Oxidative Stress; Sirtuin 3
PubMed: 31852393
DOI: 10.1161/CIRCRESAHA.119.315767 -
Circulation Research Jan 2024T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of...
BACKGROUND
T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear.
METHODS
Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmn/CD4), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmn/Foxp3), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development.
RESULTS
LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects.
CONCLUSIONS
LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
Topics: Animals; Humans; Mice; Acetates; Angiotensin II; CD4-Positive T-Lymphocytes; Desoxycorticosterone; Hypertension; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; TNF Receptor-Associated Factor 6
PubMed: 38047378
DOI: 10.1161/CIRCRESAHA.123.322835 -
Nature Communications Nov 2021Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated...
Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.
Topics: Aggression; Animals; Brain; Corticosterone; Depressive Disorder; Female; Gene Expression Profiling; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-fos; Receptors, Mineralocorticoid; Restraint, Physical; Stress, Psychological; Time Factors; Mice
PubMed: 34795225
DOI: 10.1038/s41467-021-26968-4 -
British Journal of Pharmacology Jul 2022In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major... (Review)
Review
In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major ligand of the mineralocorticoid receptor is cortisol, and the mineralocorticoid/glucocorticoid receptor balance regulates the activation of the MR pathway. Experimental mineralocorticoid receptor pathway activation using either pharmacological agents or transgenic manipulation favours retinal and choroidal pathology. In various models of retinal diseases, such as glaucomatous neuropathy, retinopathy of prematurity, ischaemic retinopathies, diabetic retinopathy and choroidal neovascularization, mineralocorticoid receptor antagonism exerts beneficial effects, demonstrating its potential in the treatment of major blinding retinal diseases. But specific formulations are required to optimize the bioavailability of mineralocorticoid receptor antagonists in various compartments of the eye, and molecular biomarkers of mineralocorticoid receptor pathway activation remain to be identified in humans to select patients amenable to clinical trials. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Diabetic Retinopathy; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid; Retina; Retinal Diseases
PubMed: 34877649
DOI: 10.1111/bph.15770 -
Cardiovascular Research Oct 2023Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence...
AIMS
Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling.
METHODS AND RESULTS
Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure.
CONCLUSIONS
Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.
Topics: Humans; Mice; Animals; Heart Failure; Desoxycorticosterone Acetate; Stroke Volume; Hypertension; Cardiomyopathies; Myeloid Cells; Leukocytes; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37314125
DOI: 10.1093/cvr/cvad093