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1.
Annu Rev Physiol ; 84: 585-610, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-35143332

RESUMEN

Mineralocorticoid receptor (MR) activation in the heart and vessels leads to pathological effects, such as excessive extracellular matrix accumulation, oxidative stress, and sustained inflammation. In these organs, the MR is expressed in cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and inflammatory cells. We review the accumulating experimental and clinical evidence that pharmacological MR antagonism has a positive impact on a battery of cardiac and vascular pathological states, including heart failure, myocardial infarction, arrhythmic diseases, atherosclerosis, vascular stiffness, and cardiac and vascular injury linked to metabolic comorbidities and chronic kidney disease. Moreover, we present perspectives on optimization of the use of MR antagonists in patients more likely to respond to such therapy and review the evidence suggesting that novel nonsteroidal MR antagonists offer an improved safety profile while retaining their cardiovascular protective effects. Finally, we highlight future therapeutic applications of MR antagonists in cardiovascular injury.


Asunto(s)
Enfermedades Cardiovasculares , Sistema Cardiovascular , Sistema Cardiovascular/metabolismo , Células Endoteliales/metabolismo , Corazón , Humanos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptores de Mineralocorticoides/metabolismo
2.
Clin Sci (Lond) ; 138(16): 1025-1038, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39092535

RESUMEN

Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet. Balcinrenone and eplerenone prevented the progression of renal damages, extracellular matrix remodeling and inflammation to a similar extent. We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation.


Asunto(s)
Eplerenona , Matriz Extracelular , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Proteoglicanos , Receptores de Mineralocorticoides , Transducción de Señal , Receptor Toll-Like 4 , Animales , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptor Toll-Like 4/metabolismo , Eplerenona/farmacología , Eplerenona/uso terapéutico , Receptores de Mineralocorticoides/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Proteoglicanos/metabolismo , Espironolactona/farmacología , Espironolactona/análogos & derivados , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Inflamación/metabolismo , Inflamación/tratamiento farmacológico
3.
Int J Mol Sci ; 24(3)2023 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-36768859

RESUMEN

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.


Asunto(s)
Cardiopatías , Insuficiencia Cardíaca , Síndrome Metabólico , Insuficiencia Renal Crónica , Masculino , Ratas , Animales , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Volumen Sistólico , Naftiridinas/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Fibrosis , Cardiopatías/tratamiento farmacológico , Hipertrofia/tratamiento farmacológico , Receptores de Mineralocorticoides/metabolismo
4.
Circ Res ; 127(3): e80-e93, 2020 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-32329663

RESUMEN

RATIONALE: Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. OBJECTIVE: We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. METHODS AND RESULTS: Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. CONCLUSIONS: These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.


Asunto(s)
Aldosterona/toxicidad , Prolapso de la Válvula Mitral/metabolismo , Válvula Mitral/efectos de los fármacos , Receptores de Mineralocorticoides/agonistas , Receptores de Mineralocorticoides/metabolismo , Anciano , Animales , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Fibrosis , Humanos , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/farmacología , Válvula Mitral/metabolismo , Válvula Mitral/patología , Prolapso de la Válvula Mitral/inducido químicamente , Prolapso de la Válvula Mitral/patología , Prolapso de la Válvula Mitral/prevención & control , Comunicación Paracrina , Fenotipo , Estudios Prospectivos , Proteoglicanos/metabolismo , Receptores de Mineralocorticoides/deficiencia , Receptores de Mineralocorticoides/genética , Transducción de Señal
5.
Int J Mol Sci ; 23(12)2022 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-35743123

RESUMEN

The beneficial effects of mineralocorticoid receptor (MR) antagonists (MRAs) for various kidney diseases are established. However, the underlying mechanisms of kidney injury induced by MR activation remain to be elucidated. We recently reported aldosterone-induced enhancement of proteoglycan expression in mitral valve interstitial cells and its association with fibromyxomatous valvular disorder. As the expression of certain proteoglycans is elevated in several kidney diseases, we hypothesized that proteoglycans mediate kidney injury in the context of aldosterone/MR pathway activation. We evaluated the proteoglycan expression and tissue injury in the kidney and isolated glomeruli of uninephrectomy/aldosterone/salt (NAS) mice. The MRA eplerenone was administered to assess the role of the MR pathway. We investigated the direct effects of biglycan, one of the proteoglycans, on macrophages using isolated macrophages. The kidney samples from NAS-treated mice showed enhanced fibrosis and increased expression of biglycan accompanying glomerular macrophage infiltration and enhanced expression of TNF-α, iNOS, Nox2, CCL3 (C-C motif chemokine ligand 3), and phosphorylated NF-κB. Eplerenone blunted these changes. Purified biglycan stimulated macrophages to express TNF-α, iNOS, Nox2, and CCL3. This was prevented by a toll-like receptor 4 (TLR4) or NF-κB inhibitor, indicating that biglycan stimulation is dependent on the TLR4/NF-κB pathway. We identified the proteoglycan biglycan as a novel target of MR involved in MR-induced glomerular injury and macrophage infiltration via a biglycan/TLR4/NF-κB/CCL3 cascade.


Asunto(s)
Enfermedades Renales , Receptor Toll-Like 4 , Aldosterona/metabolismo , Aldosterona/farmacología , Animales , Biglicano/metabolismo , Eplerenona/farmacología , Enfermedades Renales/etiología , Ratones , Antagonistas de Receptores de Mineralocorticoides/farmacología , FN-kappa B/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transducción de Señal , Cloruro de Sodio Dietético , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa
6.
Int J Mol Sci ; 21(15)2020 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-32731636

RESUMEN

Mitral valve prolapse (MVP) patients develop myocardial fibrosis that is not solely explained by volume overload, but the pathophysiology has not been defined. Mineralocorticoid receptor antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis in other heart diseases. We examined the role of MRA in myocardial fibrosis associated with myxomatous degeneration of the mitral valve. Myocardial fibrosis has been analyzed in a mouse model of mitral valve myxomatous degeneration generated by pharmacological treatment with Nordexfenfluramine (NDF) in the presence of the MRA spironolactone. In vitro, adult human cardiac fibroblasts were treated with NDF and spironolactone. In an experimental mouse, MRA treatment reduced interstitial/perivascular fibrosis and collagen type I deposition. MRA administration blunted NDF-induced cardiac expression of vimentin and the profibrotic molecules galectin-3/cardiotrophin-1. In parallel, MRA blocked the increase in cardiac non-fibrillar proteins such as fibronectin, aggrecan, decorin, lumican and syndecan-4. The following effects are blocked by MRA: in vitro, in adult human cardiac fibroblasts, NDF-treatment-induced myofibroblast activation, collagen type I and proteoglycans secretion. Our findings demonstrate, for the first time, the contribution of the mineralocorticoid receptor (MR) to the development of myocardial fibrosis associated with mitral valve myxomatous degeneration. MRA could be a therapeutic approach to reduce myocardial fibrosis associated with MVP.


Asunto(s)
Fibroblastos/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacología , Prolapso de la Válvula Mitral/metabolismo , Miocardio/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animales , Modelos Animales de Enfermedad , Fibroblastos/patología , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Prolapso de la Válvula Mitral/tratamiento farmacológico , Prolapso de la Válvula Mitral/patología , Proteínas Musculares/biosíntesis , Miocardio/patología
7.
Exp Eye Res ; 187: 107747, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31394103

RESUMEN

Preclinical and clinical evidences show that aldosterone and/or mineralocorticoid receptor (MR) over-activation by glucocorticoids can be deleterious to the retina and to the retinal pigment epithelium (RPE)-choroid complex. However, the exact molecular mechanisms driving these effects remain poorly understood and pathological consequences of chronic exposure of the retina and RPE/choroid to aldosterone have not been completely explored. We aimed to decipher the transcriptomic regulation in the RPE-choroid complex in rats in response to acute intraocular aldosterone injection and to explore the consequences of systemic chronic aldosterone exposure on the morphology and the gene regulation in RPE/choroid in mice. High dose of aldosterone (100 nM) was intravitreously injected in Lewis rat eyes in order to yield an aldosterone dose able to induce a molecular response at the apical side of the RPE-choroid complex. The posterior segment morphology was evaluated in vivo using optical coherence tomography (OCT) before and 24 h after aldosterone injection. Rat RPE-choroid complexes were used for RNA sequencing and analysis. Uninephrectomy/aldosterone/salt (NAS) model was created in wild-type C57BL/6 mice. After 6 weeks, histology of mouse posterior segments were observed ex vivo. Gene expression in the RPE-choroid complex was analyzed using quantitative PCR. Acute intravitreous injection of aldosterone induced posterior segment inflammation observed on OCT. RNA sequencing of rat RPE-choroid complexes revealed up-regulation of pathways involved in inflammation, oxidative stress and RNA procession, and down-regulation of genes involved in synaptic activity, muscle contraction, cytoskeleton, cell junction and transporters. Chronic aldosterone/salt exposure in NAS model induces retinal edema, choroidal vasodilation and RPE cell dysfunction and migration. Quantitative PCR showed deregulation of genes involved in inflammatory response, oxidative stress, particularly the NOX pathway, angiogenesis and cell contractility. Both rodent models share some common phenotypes and molecular regulations in the RPE-choroid complex that could contribute to pachychoroid epitheliopathy in humans. The difference in inflammatory status relies on different intraocular or systemic route of aldosterone administration and on the different doses of aldosterone exposed to the RPE-choroid complex.


Asunto(s)
Aldosterona/farmacología , Coroides/efectos de los fármacos , Proteínas del Ojo/genética , Regulación de la Expresión Génica/fisiología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Enfermedad Aguda , Animales , Presión Sanguínea/efectos de los fármacos , Movimiento Celular , Coroides/metabolismo , Coroides/patología , Enfermedades de la Coroides/inducido químicamente , Enfermedades de la Coroides/diagnóstico , Enfermedad Crónica , Modelos Animales de Enfermedad , Inyecciones Intravítreas , Masculino , Ratones , Ratones Endogámicos C57BL , Nefrectomía , Papiledema/inducido químicamente , Papiledema/diagnóstico , Ratas , Ratas Endogámicas Lew , Reacción en Cadena en Tiempo Real de la Polimerasa , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Análisis de Secuencia de ARN , Tomografía de Coherencia Óptica
8.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-31252520

RESUMEN

The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction and sustained decrease in renal perfusion that is partially explained by a reduction in NO bioavailability. Therefore, we aimed to explore if an endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR. Male mice with a specific endothelial sodium channel α (αENaC) subunit gene inactivation in the endothelium (endo-αENaCKO) and control littermates were subjected to bilateral renal ischemia of 22 min and were studied after 24 h of reperfusion. In control littermates, renal ischemia induced an increase in plasma creatinine and urea, augmented the kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin-2 (NGAL) mRNA levels, and produced severe tubular injury. The absence of endothelial αENaC expression prevented renal tubular injury and renal dysfunction. Moreover, endo-αENaCKO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates. In human endothelial cells, pharmacological ENaC inhibition promoted endothelial nitric oxide synthase (eNOS) coupling and activation. Altogether, these data suggest an important role for endothelial αENaC in kidney IR injury through improving eNOS activation and kidney perfusion, thus, preventing ischemic injury.


Asunto(s)
Canales Epiteliales de Sodio/genética , Daño por Reperfusión/metabolismo , Animales , Células Cultivadas , Canales Epiteliales de Sodio/deficiencia , Receptor Celular 1 del Virus de la Hepatitis A/genética , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/patología , Lipocalina 2/genética , Lipocalina 2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/metabolismo , Daño por Reperfusión/genética
9.
J Mol Cell Cardiol ; 121: 124-133, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29981797

RESUMEN

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.


Asunto(s)
Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Naftiridinas/administración & dosificación , Receptores de Mineralocorticoides/genética , Insuficiencia Renal Crónica/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Eplerenona/administración & dosificación , Insuficiencia Cardíaca Diastólica/etiología , Insuficiencia Cardíaca Diastólica/genética , Insuficiencia Cardíaca Diastólica/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Ratones , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/fisiopatología
10.
J Am Heart Assoc ; 13(12): e032971, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38842271

RESUMEN

BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.


Asunto(s)
Modelos Animales de Enfermedad , Fibrosis , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Óxido Nítrico Sintasa de Tipo III , Insuficiencia Renal Crónica , Disfunción Ventricular Izquierda , Animales , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Diástole/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Riñón/metabolismo , Fosforilación , Miocardio/metabolismo , Miocardio/patología , Ratas Sprague-Dawley , Ratas , Nefrectomía
11.
Hypertension ; 80(9): 1860-1870, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37377014

RESUMEN

BACKGROUND: The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. METHODS: a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na). RESULTS: we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2ß (calcium/calmodulin-dependent protein kinase II ß subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2ß prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. CONCLUSIONS: we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure.


Asunto(s)
Aldosterona , Hipertensión , Ratones , Animales , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Lipocalina 2/genética , Lipocalina 2/metabolismo , Riñón/metabolismo , Sodio/metabolismo , Ratones Noqueados
12.
Hypertension ; 79(2): 352-364, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34794340

RESUMEN

NGAL (neutrophil gelatinase-associated lipocalin; or lipocalin 2, Lcn2) is a novel mineralocorticoid target in the cardiovascular system. We showed that Lcn2 gene invalidation protects against proteinuria and renal injury upon mineralocorticoid excess and we hypothesized that NGAL produced from macrophages promotes the expression of chemoattractant molecules involved these renal lesions. The role of NGAL was analyzed using myeloid-specific (MΦ KO NGAL) Lcn2 knockout mice challenged with uni-nephrectomy, aldosterone, and salt (NAS) for 6 weeks. The role of the CCL5 (chemokine ligand 5) and IL4 (interleukin 4) in kidney fibrosis was studied by administration of the CCL5 receptor antagonist maraviroc or by injections of an anti-IL4 neutralizing antibody. In CTL mice, NAS increased the renal expression of extracellular matrix proteins, such as collagen I, αSMA, and fibronectin associated with interstitial fibrosis which were blunted in MΦ KO NGAL mice. The expression of CCL5 was blunted in sorted macrophages from MΦ KO NGAL mice challenged by NAS and in macrophages obtained from KO NGAL mice and challenged ex vivo with aldosterone and salt. The pharmacological blockade of the CCL5 receptor reduced renal fibrosis and the CD4+ Th cell infiltration induced by NAS. Neutralization of IL4 in NAS mice blunted kidney fibrosis and the overexpression of profibrotic proteins, such as collagen I, αSMA, and fibronectin. In conclusion, NGAL produced by macrophages plays a critical role in renal fibrosis and modulates the CCL5/IL4 pathway in mice exposed to mineralocorticoid excess.


Asunto(s)
Quimiocina CCL5/metabolismo , Interleucina-4/metabolismo , Enfermedades Renales/metabolismo , Riñón/metabolismo , Lipocalina 2/metabolismo , Macrófagos/metabolismo , Células Th2/metabolismo , Animales , Fibrosis/metabolismo , Fibrosis/patología , Riñón/patología , Enfermedades Renales/patología , Lipocalina 2/genética , Masculino , Ratones , Ratones Noqueados
13.
Metabolism ; 130: 155165, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35183546

RESUMEN

INTRODUCTION: High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not increase endothelial cell (EC) or vascular stiffness or endothelial sodium channel (EnNaC) activation in mice, presumably because aldosterone production was significantly suppressed as a result of the high salt diet. We thus hypothesized that high salt consumption along with an exogenous mineralocorticoid would substantially increase EC and vascular stiffness via activation of the EnNaC. METHODS AND RESULTS: Mice were implanted with slow-release DOCA pellets and given salt in their drinking water for 21 days. Mice with either specific deletion of the alpha subunit of EnNaC or treated with a pharmacological inhibitor of mTOR, a downstream signaling molecule involved in mineralocorticoid receptor activation of EnNaC, were studied. DOCA-salt treated control mice had increased blood pressure, EC Na+ transport activity, EC and arterial stiffness, which were attenuated in both the αEnNaC-/- and mTOR inhibitor treated groups. Further, depletion of αEnNaC prevented DOCA-salt-induced impairment in EC-dependent vascular relaxation. CONCLUSION: While high salt consumption alone does not cause EC or vascular stiffening, the combination of EC MR activation and high salt causes activation of EnNaC which increases EC and arterial stiffness and impairs vascular relaxation. Underlying mechanisms appear to include mTOR signaling.


Asunto(s)
Acetato de Desoxicorticosterona , Hipertensión , Rigidez Vascular , Animales , Presión Sanguínea , Células Endoteliales/metabolismo , Canales Epiteliales de Sodio , Ratones , Sodio
14.
Front Physiol ; 13: 859812, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35464084

RESUMEN

Obesity and/or metabolic diseases are frequently associated with chronic kidney disease and several factors associated with obesity may contribute to proteinuria and extracellular matrix production. Mineralocorticoid receptor antagonists have proven their clinical efficacy in diabetic kidney disease with preclinical data suggesting that they may also be efficient in non-diabetic chronic kidney disease associated to metabolic diseases. In the present study we developed a novel mouse model combining severe nephron reduction and High Fat Diet challenge that led to chronic kidney disease with metabolic alterations. We showed that the Mineralocorticoid Receptor antagonist canrenoate improved metabolic function, reduced albuminuria and prevented the synergistic effect of high fat diet on renal fibrosis and inflammation in chronic kidney disease mice.

15.
Sci Rep ; 11(1): 2591, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510370

RESUMEN

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.


Asunto(s)
Lipocalina 2/antagonistas & inhibidores , Lipocalina 2/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Masculino , Ratones
16.
Am J Hypertens ; 31(11): 1165-1174, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30192914

RESUMEN

Activation of the mineralocorticoid receptor (MR) in the distal nephron by its ligand, aldosterone, plays an important role in sodium reabsorption and blood pressure regulation. However, expression of the MR goes beyond the kidney. It is expressed in a variety of other tissues in which its activation could lead to tissue injury. Indeed, MR activation in the cardiovascular (CV) system has been shown to promote hypertension, fibrosis, and inflammation. Pharmacological blockade of the MR has protective effects in several animal models of CV disease. Furthermore, the use of MR antagonists is beneficial for heart failure patients, preventing mortality and morbidity. A better understanding of the implications of the MR in the setting of CV diseases is critical for refining treatments and improving patient care. The mechanisms involved in the deleterious effects of MR activation are complex and include oxidative stress, inflammation, and fibrosis. This review will discuss the pathological role of the MR in the CV system and the major mechanisms underlying it.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Sistema Cardiovascular/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptores de Mineralocorticoides/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Humanos , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Receptores de Mineralocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos
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