Regulation of epithelial Na<sup>+</sup>channels by adrenal steroids: mineralocorticoid and glucocorticoid effects

Frindt, Gustavo; Palmer, Lawrence G.

doi:10.1152/ajprenal.00480.2011

Cited by 40 publications

(33 citation statements)

References 38 publications

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“…It has been well documented that cortisol exerts its activity by increasing the number of ionocytes, and by stimulating the transcription, translation, and activity of ion transporters [32], [39], [44], [45], [57]–[63]. Whether these control pathways are mediated by GR, MR or both has been a long-term subject of debate, one that has been investigated primarily by pharmacological approaches; however, the evidence accumulated to date has remained inconclusive due to its conflicting nature.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

et al. 2013

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Cortisol is the major endogenous glucocorticoid (GC) both in human and fish, mediated by corticosteroid receptors. Due to the absence of aldosterone production in teleost fish, cortisol is also traditionally accepted to function as mineralocorticoid (MC); but whether it acts through the glucocorticoid receptor (GR) or the mineralocorticoid receptor (MR) remains a subject of debate. Here, we used loss-of-function and rescue assays to determine whether cortisol affects zebrafish epidermal ionocyte development and function via the GR and/or the MR. GR knockdown morphants displayed a significant decrease in the major ionocytes, namely Na+-K+-ATPase-rich cells (NaRCs) and H+-ATPase-rich cells (HRCs), as well as other cells, including epidermal stem cells (ESCs), keratinocytes, and mucus cells; conversely, cell numbers were unaffected in MR knockdown morphants. In agreement, GR morphants, but not MR morphants, exhibited decreased NaRC-mediated Ca2+ uptake and HRC-mediated H+ secretion. Rescue via GR capped mRNA injection or exogenous cortisol incubation normalized the number of epidermal ionocytes in GR morphants. We also provide evidence for GR localization in epidermal cells. At the transcript level, GR mRNA is ubiquitously expressed in gill sections and present in both NaRCs and HRCs, supporting the knockdown and functional assay results in embryo. Altogether, we have provided solid molecular evidence that GR is indeed present on ionocytes, where it mediates the effects of cortisol on ionocyte development and function. Hence, cortisol-GR axis performs the roles of both GC and MC in zebrafish skin and gills.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

et al. 2013

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“…Chronically elevated plasma sodium without any evidence of increased dietary intake or greater net renal retention suggests a more efficient continuous reabsorption at an alternative site, likely the gastrointestinal (rather than salivary) tract. It is well established that glucocorticoids regulate sodium uptake across the gut via induction of expression of a number of sodium/proton antiporters, particularly SLC9A3 at specific locations along the gastrointestinal tract including ileum and proximal colon [28]–[30]. The proximal colon is also a target for aldosterone induced transcriptional upregulation of SLC9A3 [31] and its activation in brush border membrane vesicles (BBMVs), by incubation with aldosterone, results in a considerable increase in sodium transport that is not observed when the BBMVs are derived from the ileum.…”

Section: Discussionmentioning

confidence: 99%

Excess Maternal Salt Intake Produces Sex-Specific Hypertension in Offspring: Putative Roles for Kidney and Gastrointestinal Sodium Handling

et al. 2013

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Hypertension is common and contributes, via cardiovascular disease, towards a large proportion of adult deaths in the Western World. High salt intake leads to high blood pressure, even when occurring prior to birth – a mechanism purported to reside in altered kidney development and later function. Using a combination of in vitro and in vivo approaches we tested whether increased maternal salt intake influences fetal kidney development to render the adult individual more susceptible to salt retention and hypertension. We found that salt-loaded pregnant rat dams were hypernatraemic at day 20 gestation (147±5 vs. 128±5 mmoles/L). Increased extracellular salt impeded murine kidney development in vitro, but had little effect in vivo. Kidneys of the adult offspring had few structural or functional abnormalities, but male and female offspring were hypernatraemic (166±4 vs. 149±2 mmoles/L), with a marked increase in plasma corticosterone (e.g. male offspring; 11.9 [9.3–14.8] vs. 2.8 [2.0–8.3] nmol/L median [IQR]). Furthermore, adult male, but not female, offspring had higher mean arterial blood pressure (effect size, +16 [9–21] mm Hg; mean [95% C.I.]. With no clear indication that the kidneys of salt-exposed offspring retained more sodium per se, we conducted a preliminary investigation of their gastrointestinal electrolyte handling and found increased expression of proximal colon solute carrier family 9 (sodium/hydrogen exchanger), member 3 (SLC9A3) together with altered faecal characteristics and electrolyte handling, relative to control offspring. On the basis of these data we suggest that excess salt exposure, via maternal diet, at a vulnerable period of brain and gut development in the rat neonate lays the foundation for sustained increases in blood pressure later in life. Hence, our evidence further supports the argument that excess dietary salt should be avoided per se, particularly in the range of foods consumed by physiologically immature young.

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“…4 Mechanisms by which these hormones regulate renal ENaCs have been the focus of numerous reviews. 2, 3, 9, 26–29 Aldosterone increases expression of the α subunit as well as many other proteins, including the serum and glucocorticoid regulated kinase (SGK1), and the adaptors glucocorticoid-induced leucine zipper 1 (GILZ1) and connector enhancer of kinase suppressor of Ras isoform 3, which enhance surface expression of channels. 2, 30–35 …”

Section: Expression and Regulation Of Enac In The Distal Nephronmentioning

confidence: 99%

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

et al. 2014

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This review is focused on the expression and regulation of amiloride-sensitive sodium channels in the epithelial cells of the aldosterone-sensitive distal nephron (ENaC) and amiloride-sensitive sodium channel activity in vascular endothelial and smooth muscle cells. Guyton’s hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. With the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, the main components of the aldosterone- and angiotensin-dependent sodium transporters have been identified over the past 20 years. Proteolytic processing of the ENaC external domain, and inhibition by increased sodium concentrations are important features of the ENaC complexes expressed in the distal nephron. In contrast, amiloride-sensitive sodium channels expressed in the vascular system are activated by increased external sodium concentrations, resulting in changes in the mechanical properties and function of endothelial cells. Mechano-sensitivity and shear stress affect both epithelial and vascular sodium channel activity. The synergistic effects and complementary regulation of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and may reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. We summarize the recent evidence in this review that describes the central role of amiloride-sensitive sodium channels in the efferent (e.g., vascular) and afferent (e.g., epithelial) arms of this homeostatic system.

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Regulation of epithelial Na⁺channels by adrenal steroids: mineralocorticoid and glucocorticoid effects

Abstract: Frindt G, Palmer LG. Regulation of epithelial Na ϩ channels by adrenal steroids: mineralocorticoid and glucocorticoid effects.

Cited by 40 publications

References 38 publications

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

Excess Maternal Salt Intake Produces Sex-Specific Hypertension in Offspring: Putative Roles for Kidney and Gastrointestinal Sodium Handling

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

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Regulation of epithelial Na+channels by adrenal steroids: mineralocorticoid and glucocorticoid effects

Abstract: Frindt G, Palmer LG. Regulation of epithelial Na ϩ channels by adrenal steroids: mineralocorticoid and glucocorticoid effects.

Cited by 40 publications

References 38 publications

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

Glucocorticoid Receptor, but Not Mineralocorticoid Receptor, Mediates Cortisol Regulation of Epidermal Ionocyte Development and Ion Transport in Zebrafish (Danio Rerio)

Excess Maternal Salt Intake Produces Sex-Specific Hypertension in Offspring: Putative Roles for Kidney and Gastrointestinal Sodium Handling

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

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Regulation of epithelial Na⁺channels by adrenal steroids: mineralocorticoid and glucocorticoid effects