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Frederic Jaisser - One of the best experts on this subject based on the ideXlab platform.

  • Vascular Mineralocorticoid Receptor activation and disease.
    Experimental eye research, 2019
    Co-Authors: Jonatan Barrera-chimal, Frederic Jaisser
    Abstract:

    Abstract Mineralocorticoid Receptor activation in endothelial and smooth muscle cells can promote vascular disease by increasing oxidative stress, promoting inflammation, accelerating vascular stiffness, remodeling, and calcification, altering vessel responsiveness to various vasoactive factors, thus altering vascular tone and blood pressure, and by altering angiogenesis. Here, we review the recent evidence highlighting the impact of vascular Mineralocorticoid Receptor activation in pathological situations, including kidney injury, vascular injury associated with metabolic diseases, atherosclerosis, cerebral vascular injury during hypertension, vascular stiffening and aging, pulmonary hypertension, vascular calcification, cardiac remodeling, wound healing, inflammation, thrombosis, and disorders related to angiogenic defects in the eye. The possible mechanisms implicating Mineralocorticoid Receptor activation in various vascular disorders are discussed. Altogether, recent evidence points towards pharmacological Mineralocorticoid Receptor inhibition as a strategy to treat diseases in which overactivation of the Mineralocorticoid Receptor in endothelial and/or smooth muscle cells may play a pivotal role.

  • Mineralocorticoid Receptor antagonists and kidney diseases pathophysiological basis
    Kidney International, 2019
    Co-Authors: Jonatan Barrerachimal, Sophie Girerd, Frederic Jaisser
    Abstract:

    Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin Receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid Receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that Mineralocorticoid Receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.

  • Mineralocorticoid Receptor antagonists and kidney diseases: pathophysiological basis
    Kidney International, 2019
    Co-Authors: Jonatan Barrera-chimal, Sophie Girerd, Frederic Jaisser
    Abstract:

    Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin Receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid Receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that Mineralocorticoid Receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  • The myeloid Mineralocorticoid Receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 Receptor signaling
    Kidney International, 2018
    Co-Authors: Jonatan Barrera-chimal, Peter Kolkhof, Sebastian M Lechner, Soumaya El Moghrabi, Gabriel R. Estrela, Shiem Kaaki, Sébastien Giraud, Thierry Hauet, Frederic Jaisser
    Abstract:

    Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal Mineralocorticoid Receptor antagonist finerenone or selective myeloid Mineralocorticoid Receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid Mineralocorticoid Receptor-deficient mice. Moreover, the inflammatory population of CD11b + , F4/80 + , Ly6C high macrophages was also reduced. Mineralocorticoid Receptor inhibition promoted increased IL-4 Receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by Mineralocorticoid Receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using Mineralocorticoid Receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.

  • nonsteroidal Mineralocorticoid Receptor antagonist finerenone protects against acute kidney injury mediated chronic kidney disease
    Hypertension, 2017
    Co-Authors: Lionel Lattenist, Peter Kolkhof, Sebastian M Lechner, Smail Messaoudi, Alan Le Mercier, Soumaya El Moghrabi, Sonia Prince, Frederic Jaisser, Norma A. Bobadilla, Jonatan Barrerachimal
    Abstract:

    Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid Receptor antagonism has shown to be helpful against renal IR conseque...

Bertram Pitt - One of the best experts on this subject based on the ideXlab platform.

Peter J. Fuller - One of the best experts on this subject based on the ideXlab platform.

  • Pseudohypoaldosteronism: Molecular Characterization of the Mineralocorticoid Receptor
    The Journal of clinical endocrinology and metabolism, 1994
    Co-Authors: Paul A. Komesaroff, Karen Verity, Peter J. Fuller
    Abstract:

    Mineralocorticoid resistance (pseudohypoaldosteronism) is a rare condition first described in 1958 and associated with failure to thrive, salt wasting, and dehydration in infancy. In the index case it has previously been shown that binding of aldosterone to Mineralocorticoid Receptors in peripheral blood lymphocytes is absent; here, we report results of the molecular characterization of the Mineralocorticoid Receptor in this patient. Genomic DNA extracted from peripheral blood lymphocytes was subjected to Southern blot analysis after digestion with various restriction enzymes. There was no evidence of a major gene rearrangement or deletion. Oligonucleotide primers were designed on the basis of the published human complementary DNA sequence to cover the entire open reading frame of the Mineralocorticoid Receptor (MR). Total messenger ribonucleic acid (RNA) from lymphocytes was subjected to reverse transcription and amplification using the reverse transcriptase-polymerase chain reaction; the resulting fragm...

  • Pseudohypoaldosteronism: Molecular Characterization of the Mineralocorticoid Receptor
    The Journal of clinical endocrinology and metabolism, 1994
    Co-Authors: Paul A. Komesaroff, Karen Verity, Peter J. Fuller
    Abstract:

    Mineralocorticoid resistance (pseudohypoaldosteronism) is a rare condition first described in 1958 and associated with failure to thrive, salt wasting, and dehydration in infancy. In the index case it has previously been shown that binding of aldosterone to Mineralocorticoid Receptors in peripheral blood lymphocytes is absent; here, we report results of the molecular characterization of the Mineralocorticoid Receptor in this patient. Genomic DNA extracted from peripheral blood lymphocytes was subjected to Southern blot analysis after digestion with various restriction enzymes. There was no evidence of a major gene rearrangement or deletion. Oligonucleotide primers were designed on the basis of the published human complementary DNA sequence to cover the entire open reading frame of the Mineralocorticoid Receptor (MR). Total messenger ribonucleic acid (RNA) from lymphocytes was subjected to reverse transcription and amplification using the reverse transcriptase-polymerase chain reaction; the resulting fragments were then purified, subcloned, and sequenced. The patient showed no abnormality in the complementary DNA sequence corresponding to the open reading frame of the MR molecule compared with the published sequence. In addition, semiquantitative assessment of the patient's MR messenger RNA based on the reverse transcriptase-polymerase chain reaction technique suggested that he was producing MR RNA in roughly normal quantities. The mechanism of Mineralocorticoid resistance in this case, therefore, remains uncertain, and the possibility must be considered that the underlying abnormality is not in the MR gene, but in an independent gene acting through yet to be characterized processes.

Toshiro Fujita - One of the best experts on this subject based on the ideXlab platform.

  • Two Mineralocorticoid Receptor-Mediated Mechanisms of Pendrin Activation in Distal Nephrons.
    Journal of the American Society of Nephrology : JASN, 2020
    Co-Authors: Nobuhiro Ayuzawa, Wakako Kawarazaki, Mitsuhiro Nishimoto, Kohei Ueda, Daigoro Hirohama, Tatsuo Shimosawa, Takeshi Marumo, Toshiro Fujita
    Abstract:

    Background Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system. Methods Using mice with Mineralocorticoid Receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via Mineralocorticoid Receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension. Results Deletion of Mineralocorticoid Receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell-specific Mineralocorticoid Receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of Mineralocorticoid Receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated Mineralocorticoid Receptor-epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP. Conclusions In conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through Mineralocorticoid Receptor activation in intercalated cells and by alkalosis through Mineralocorticoid Receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.

  • Role of Rac1–Mineralocorticoid-Receptor signalling in renal and cardiac disease
    Nature reviews. Nephrology, 2013
    Co-Authors: Miki Nagase, Toshiro Fujita
    Abstract:

    The Rho-family small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), has been implicated in renal and cardiac disease. Rac1 activation in podocytes has been shown in several models of proteinuric kidney disease and a concept involving motile podocytes has been proposed. Evidence also exists for a critical role of Rac1-mediated oxidative stress in cardiac hypertrophy, cardiomyopathy and arrhythmia, and of the aldosterone-Mineralocorticoid-Receptor system in proteinuria and cardiac disorders. However, plasma aldosterone concentrations are not always increased in these conditions and the mechanisms of Mineralocorticoid-Receptor overactivation are difficult to determine. Using knockout mice, we identified a novel mechanism of Rac1-mediated podocyte impairment; Rac1 potentiates the activity of the Mineralocorticoid Receptor, thereby accelerating podocyte injury. We subsequently demonstrated that the Rac1-Mineralocorticoid-Receptor pathway contributes to ligand-independent Mineralocorticoid-Receptor activation in several animal models of kidney and cardiac injury. Hyperkalaemia is a major concern associated with the use of Mineralocorticoid-Receptor antagonists; however, agents that modulate the activity of the Rac1-Mineralocorticoid-Receptor pathway in target cells, such as cell-type-specific Rac inhibitors and selective Mineralocorticoid-Receptor modulators, could potentially be novel therapeutic candidates with high efficacy and a low risk of adverse effects in patients with renal and cardiac diseases.

  • Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes Role of Small GTPase Rac1
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Miki Nagase, Shigetaka Yoshida, Wakako Kawarazaki, Nobuhiro Ayuzawa, Kohei Ueda, Kenichi Ishizawa, Toshiro Fujita
    Abstract:

    Overactivation of the Mineralocorticoid Receptor signaling is implicated in cardiovascular disease, including hypertensive heart disease. Oxidative stress is suggested to augment Mineralocorticoid Receptor signal transduction, but the precise mechanisms remain unclear. Mineralocorticoid Receptor activity is regulated by multiple factors, in addition to plasma ligand levels. We previously identified Rac1 GTPase as a modulator of Mineralocorticoid Receptor activity. Here we show that oxidative stress induces Mineralocorticoid Receptor activation in a ligand-independent, Rac1-depenent manner in cardiomyocytes. Oxidant stress was induced in rat cultured cardiomyocytes (H9c2) by l-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. BSO depleted intracellular glutathione and concomitantly increased reactive oxygen species (199%; P

  • Modification of Mineralocorticoid Receptor function by Rac1 GTPase: implication in proteinuric kidney disease
    Nature medicine, 2008
    Co-Authors: Shigeru Shibata, Miki Nagase, Shigetaka Yoshida, Wakako Kawarazaki, Hidetake Kurihara, Hirotoshi Tanaka, Jun Miyoshi, Yoshimi Takai, Toshiro Fujita
    Abstract:

    Blockade of Mineralocorticoid Receptor has been shown to improve the clinical outcomes of proteinuric kidney diseases. However, little is known about the regulation of Mineralocorticoid Receptor-dependent transcriptional activity in renal disease. Here we identify a new role for Rac1, a member of the Rho family GTPases, as a potent activator of Mineralocorticoid Receptor signal transduction both in vitro and in vivo. Transient transfection assays in HEK 293 cells revealed that constitutively active Rac1 (CA-Rac1) enhanced Mineralocorticoid Receptor-dependent reporter activity, which was accompanied by increased nuclear translocation of Mineralocorticoid Receptor. CA-Rac1 facilitated Mineralocorticoid Receptor nuclear accumulation also in podocytes via p21-activated kinase phosphorylation. In mice lacking Rho GDP-dissociation inhibitor-alpha (Arhgdia(-/-) mice), renal abnormalities, including heavy albuminuria and podocyte damage, were associated with increased Rac1 (but not RhoA) and Mineralocorticoid Receptor signaling in the kidney, without alteration in systemic aldosterone status. Pharmacological intervention with a Rac-specific small-molecule inhibitor diminished Mineralocorticoid Receptor overactivity and renal damage in this model. Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by Mineralocorticoid Receptor blockade, confirming the pathological role of Rac1-Mineralocorticoid Receptor interaction. Our results provide evidence that signaling cross-talk between Rac1 and Mineralocorticoid Receptor modulates Mineralocorticoid Receptor activity and identify Rac1 as a therapeutic target for chronic kidney disease.

Richard P Lifton - One of the best experts on this subject based on the ideXlab platform.

  • activating Mineralocorticoid Receptor mutation in hypertension exacerbated by pregnancy
    Science, 2000
    Co-Authors: David S. Geller, Anita Farhi, Nikki Pinkerton, Michael Fradley, Michael L Moritz, Adrian Spitzer, Gretchen Meinke, Francis T F Tsai, Paul B Sigler, Richard P Lifton
    Abstract:

    Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the Mineralocorticoid Receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters Receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type Receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone Receptors, suggesting its general role in Receptor activation.

  • mutations in the Mineralocorticoid Receptor gene cause autosomal dominant pseudohypoaldosteronism type i
    Nature Genetics, 1998
    Co-Authors: David S. Geller, Juan Rodriguezsoriano, Alfredo Vallo Boado, Soren Schifter, Milan Bayer, Sue S Chang, Richard P Lifton
    Abstract:

    Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal renal salt wasting with dehydration, hypotension, hyperkalaemia and metabolic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manifestations persisting into adulthood. This form is caused by loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial sodium channel (ENaC; refs 2,3). Autosomal dominant or sporadic PHA1 is a milder disease that remits with age. Among six dominant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutations, implicating mutations in other genes. As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the Mineralocorticoid Receptor, we have screened the Mineralocorticoid Receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds. These include two frameshift mutations (one a de novo mutation), two premature termination codons and one splice donor mutation. These mutations segregate with PHA1 and are not found in unaffected subjects. These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of Mineralocorticoid Receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation.