Salt and gene expression: evidence for [Na+]i/[K+]i-mediated signaling pathways

Orlov, Sergei N.; Hamet, Pavel

doi:10.1007/s00424-014-1650-8

Cited by 31 publications

(16 citation statements)

References 91 publications

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“…Activation (39). It has been shown also that agonist-induced COX-2 expression is mediated by intracellular Ca 2ϩ (36,58).…”

Section: Ouabain Increases Cox-2 Expression and Activates Pka In Humamentioning

confidence: 99%

“…3A), the effect that was observed at long-term treatment (24 -48 h) but not at short-term treatment (up to 6 h). Because such cell shape changes may associate with cell death, and because ouabain is known to induce apoptosis of various but not all cell types (38,39), we examined a potential cytotoxic effect of ouabain on HLF by measuring the release of LDH. As shown in Fig.…”

Section: Ouabain Increases Cox-2 Expression and Activates Pka In Humamentioning

confidence: 99%

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Regulation of myofibroblast differentiation by cardiac glycosides

Reed

Кольцова

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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] ratio may promote the expression of cyclooxygenase-2 (COX-2), a critical enzyme in the synthesis of prostaglandins. Given antifibrotic effects of prostaglandins through activation of protein kinase A (PKA), we examined if cardiac glycosides stimulate COX-2 expression in human lung fibroblasts and how they affect myofibroblast differentiation. Ouabain stimulated a profound COX-2 expression and a sustained PKA activation, which was blocked by COX-2 inhibitor or by COX-2 knockdown. Ouabain-induced COX-2 expression and PKA activation were abolished by the inhibitor of the Na ϩ /Ca 2ϩ exchanger, KB-R4943. Ouabain inhibited transforming growth factor-␤ (TGF-␤)-induced Rho activation, stress fiber formation, serum response factor activation, and the expression of smooth muscle ␣-actin, collagen-1, and fibronectin. These effects were recapitulated by an increase in intracellular [Na ϩ ]/[K ϩ ] ratio through the treatment of cells with K ϩ -free medium or with digoxin. Although inhibition of COX-2 or of the Na ϩ /Ca 2ϩ exchanger blocked ouabain-induced PKA activation, this failed to reverse the inhibition of TGF-␤-induced Rho activation or myofibroblast differentiation by ouabain. Together, these data demonstrate that ouabain, through the increase in intracellular [Na ϩ ]/[K ϩ ] ratio, drives the induction of COX-2 expression and PKA activation, which is accompanied by a decreased Rho activation and myofibroblast differentiation in response to TGF-␤. However, COX-2 expression and PKA activation are not sufficient for inhibition of the fibrotic effects of TGF-␤ by ouabain, suggesting that additional mechanisms must exist. ouabain; digoxin; intracellular sodium-to-potassium ion ratio; cyclooxygenase-2 IDIOPATHIC PULMONARY FIBROSIS (IPF) is a progressive fatal disease characterized by parenchymal fibrosis and structural distortion of the lungs. Age-adjusted mortality due to pulmonary fibrosis is increasing, and it poses a vexing clinical challenge given the lack of efficacious therapy. IPF is thought to be a disorder of abnormal wound healing (54), in which the initial trigger to the fibrotic response is injury to the alveolar epithelial cell, followed by an exuberant nonresolving woundhealing response (50). Injury of alveolar epithelial cells is thought to result in the elaboration of a fibrinous provisional matrix and activation of several proinflammatory, procoagulant, and profibrotic mediators, of which transforming growth factor-␤1 (TGF-␤1) is the most established (47). Fibroblasts, under stimulation of TGF-␤1, respond by altering their gene expression profile with de novo expression of cytoskeletal and contractile proteins normally found within smooth muscle (SM) cells, modified focal adhesion complexes, and components of the extracellular matrix (18,27). These SM-like fibroblasts are called myofibroblasts and display a phenotype that is in an intermediate state between fibroblasts and SM cells (10,19). Several cytoskeletal and SM proteins are expressed in myofibroblasts, including SM ␣-actin, the most established m...

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“…Activation (39). It has been shown also that agonist-induced COX-2 expression is mediated by intracellular Ca 2ϩ (36,58).…”

Section: Ouabain Increases Cox-2 Expression and Activates Pka In Humamentioning

confidence: 99%

Section: Ouabain Increases Cox-2 Expression and Activates Pka In Humamentioning

confidence: 99%

Regulation of myofibroblast differentiation by cardiac glycosides

Reed

Кольцова

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Our previous analyses demonstrated linearly enhanced expression of tubular ENaCs in accordance with genotype and oral salt intake, which is abolished by amiloride treatment. These findings suggest that the amplified intracellular sodium signaling resulted in ENaC gene transcription, which is known as excitation and transcription coupling of monovalent cations [26,27,28,29]. ENaC is considered a major effector of aldosterone-mediated sodium reabsorption and fluid regulation.…”

Section: Discussionmentioning

confidence: 99%

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Kino

Ishigami

Murata

et al. 2017

IJMS

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The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination.

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“…86 Up-to-now, there are no reports on mutations of NKCC2 and other renal-specific CCCs in patients with essential hypertension. Schiebl and co-workers found that in mice differential splicing of NKCC2 pre-mRNA is modulated by dietary salt intake, 87 which may be triggered by recently discovered [Na + ] i /[K + ] i -mediated excitation-transcription coupling (for review, see 88 ). Enhanced tubular reabsorption of salt and osmotically-obliged water is important determinant of obesity-related hypertension.…”

Section: Functional Implications Of Nkccsmentioning

confidence: 99%

NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension

et al. 2015

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This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.

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Salt and gene expression: evidence for [Na+]i/[K+]i-mediated signaling pathways

Cited by 31 publications

References 91 publications

Regulation of myofibroblast differentiation by cardiac glycosides

Regulation of myofibroblast differentiation by cardiac glycosides

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension

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