Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio Texas 78229-3900
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ABSTRACT |
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The systemic actions of aldosterone are well documented; however, in comparison, our understanding of the cellular and molecular mechanisms by which aldosterone orchestrates these actions is rudimentary. Aldosterone exerts most of its physiological actions by modifying gene expression. It is now apparent that aldosterone represses almost as many genes as it induces. Several aldosterone-sensitive genes, including serum and glucocorticoid-inducible kinase (sgk) and small, monomeric Kirsten Ras GTP-binding protein (Ki-ras) have recently been identified. The molecular mechanisms and elements bestowing corticosteroid sensitivity on these and many other genes are becoming clear. Induction of Ki-Ras and Sgk is necessary and sufficient for some portion of aldosterone action in epithelia. These two signaling factors are components of a converging pathway with phosphatidylinositol 3-kinase positioned between them that enables both stabilizing the epithelial Na+ channel (ENaC) in the open state as well as increasing the number of ENaC in the apical membrane. This aldosterone-induced signaling pathway contains many potential sites for feedback regulation and cross talk from other cascades and potentially impinges directly on the activity of transport proteins and/or cellular differentiation to modify electrolyte transport.
mineralocorticoid; Sgk; Ki-Ras; corticosteroid hormone-induced factor; sodium-potassium-adenosinetriphosphatase; NEDD4; epithelial sodium channel; epithelial; hypertension; transport; sodium absorption; potassium secretion
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INTRODUCTION |
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THE ADRENAL CORTICOSTEROID HORMONE aldosterone plays a pivotal role in homeostasis. This is particularly apparent when one considers that dysfunctional regulation of aldosterone secretion and inappropriate activity of aldosterone effectors are involved in many human diseases associated with electrolyte and fluid imbalance.1 In addition, aldosterone has attracted much attention lately as a possible mediator of pathological heart remodeling (129). Tissues targeted by aldosterone include cardiac fibroblasts and myocytes, neurons and their support cells, smooth muscle, endothelial cells, and adipose tissue (see Refs. 58, 70, 176, and 177 for further reference). Electrically tight epithelial monolayers, such as the renal distal tubule and collecting duct system, distal colon, and those in salivary glands, are considered classic aldosterone target tissues. Aldosterone action in these tissues, as well as in toad bladder and frog skin, has been the focus of much important investigation over the last half-century. Thus the natriferic and kaliuretic effects of aldosterone have long been established. In this regard, aldosterone, acting as a mineralocorticoid, targets epithelial cells to increase Na+ (re)absorption and K+ secretion. It is striking that all known forms of Mendelian hypertension in humans result from aberrant regulation of aldosterone or its downstream effectors that implement aldosterone's signal in sodium homeostasis (reviewed in Refs. 68 and 97). The interested reader has many excellent contemporary review articles available for a discussion of the effects of aldosterone at the systemic, tissue, cellular, and molecular levels and for a history of important findings in this field (51, 52, 58, 70, 176, 177). The scope of the present review is to summarize and discuss the results of numerous recent studies investigating the cellular and molecular mechanisms of aldosterone action. The review focuses primarily on the intracellular signal transduction pathways initiated by aldosterone and the relationship of aldosterone-sensitive signaling factors to each other and their final effectors, including the luminal epithelial Na+ channel (ENaC), secretory K+ channel, and serosal Na+/K+-ATPase. Only advances in our understanding of the classic genomic mechanism of aldosterone action in epithelial cells are considered. Because several comprehensive reviews have been published recently in this journal (12, 51, 139, 177), background concepts underpinning regulation of ENaC and other aldosterone-sensitive effectors, as well as mineralocorticoid specificity and the actions and regulation of nuclear receptors and their accessory proteins, are explicitly not (re-)covered in great detail.
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ALDOSTERONE REGULATES GENE EXPRESSION |
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Aldosterone and other adrenal corticosteroids exert many of their physiological actions through modulation of gene expression. This results in a substantial lag period (~0.5-1 h) preceding overt changes in cellular activity. Similar to other steroids, aldosterone also affects cellular activity through faster (<1 min), nongenomic actions mediated presumably by distinct plasma membrane/cytosolic receptors. Nongenomic actions, while important, are for the most part beyond the focus of the present review. (The interested reader is referred to Refs. 51, 57, 70, 137, and 188 for further development of this topic.)
Molecular Mechanisms of Action
Inhibitors of transcription and translation, as well as other experimental maneuvers, have been employed to definitively demonstrate that induction of gene expression is necessary, in part, for aldosterone action in epithelia (reviewed in Refs. 51, 137, 176, and 177). However, the contrary view, that gene repression is needed, in part, for aldosterone action, has been more difficult to demonstrate. This has arisen primarily because genes negatively influenced by aldosterone have not been well described in the past. Recently, a number of aldosterone-repressed transcripts have been identified (135, 154). It is now apparent that aldosterone represses almost as many genes as it induces. It follows, then, that aldosterone-sensitive gene repression plays an important but yet undefined role in the final cellular response.Aldosterone, as well as other corticosteroid hormones, binds cytosolic
steroid receptors that translocate to the nucleus in a ligand-dependent
manner (reviewed in Refs. 51, 57, and
58). Once in the nucleus, corticosteroid receptors function as
transcription factors through interaction with genomic DNA at a
steroid-response element (SRE; consensus sequence AGAACAnnnTGTTCT).
Aldosterone is a ligand for two distinct but similar types of nuclear
receptors: the mineralocorticoid receptor (MR) and the glucocorticoid
receptor (-isoform; GR
). Glucocorticoids, as well, are ligands
for these receptors. It is well recognized that circulating levels of
glucocorticoids are in excess of those of mineralocorticoids by 100- to
1,000-fold. In contrast to GR, which is ubiquitous, MR expression is
confined primarily to epithelial cells. Thus circulating levels of
corticosteroids and receptor expression patterns often define the
cellular specificity of the glucocorticoid response mediated by GR. The
cellular mechanism(s) specifying a mineralocorticoid response are more
complex, considering that all cells expressing MR also express GR
(reviewed in Refs. 51, 57, and
58).
Corticosteroids have similar affinities for both MR and GR, although,
on- and off-rates, ligand-receptor half-lives, association with
accessory proteins, and trans-activating potential differ. The ligand-independent GR acts as a dominant negative regulator of
both GR
and MR (7). The physiological significance of
GR
to aldosterone signaling is unclear at this time. Both MR and GR
form homo- and heterodimers with each other and other accessory factors. It has been speculated that unique receptor complexes may
target distinct cis-acting elements (99, 172).
Although it is commonly accepted that MR and GR are capable of
mediating trans-activation through a common SRE, the concept
that these receptors also target unique cis-acting elements
remains quite controversial.
A novel MR splice variant that lacks a ligand-binding domain (MR5,6)
has recently been described (196). MR
5,6 is highly expressed (relative to other tissues) in the kidney. MR
5,6 forms dimers with both MR and GR, with dimers binding DNA at the SRE and
trans-activating in a ligand-independent manner. Thus
MR
5,6 appears to have the opposite function of GR
. It has been
hypothesized that this novel MR variant plays a role in defining
receptor specificity; however, the role of MR
5,6 in a
mineralocorticoid-specific response remains somewhat ambiguous,
considering that it potentiates both MR and GR
trans-activating ability to a similar degree. Several MR
mRNA species, some of which encode unique proteins, have now been
identified in various mammalian tissues (23, 90, 93, 195,
201). It is likely that all of these transcripts arise from
differential splicing or alternative transcription start sites within a
common gene. A good understanding of the physiological significance of
each type of MR isoform remains elusive at this time. However, if the
transcripts encoding unique proteins result in MR isoforms with
different specificities for corticosteroids, accessory proteins, and
SRE with distinct trans-acting capabilities, then they could
play a role in defining specificity. Distinct promotors also have been
reported to drive MR expression in a tissue-specific manner
(93). These promotors enable MR levels in disparate
tissues to be varied independently of each other. In addition, nuclear
corticosteroid receptors are modified at the posttranslation level.
Indeed, cAMP signaling via protein kinase A leads to phosphorylation of
MR, with phosphorylated receptors having greater
trans-activating potential compared with unmodified receptors (108). Thus further investigation of the
function, posttranslational regulation, and transcriptional control of
MR isoforms is needed to gain more precise insight into the
physiological role played by each during a mineralocorticoid response.
Two distinct molecular mechanisms as depicted in Fig.
1 are widely accepted to define the
actions of nuclear receptors on gene expression: 1) the
classic mechanisms involving trans-activation and
trans-repression via interaction with cognate DNA-binding sites, such as SRE and 2) mechanisms of transcription
interference and synergy mediated by protein-protein interactions
between corticosteroid receptors and other trans-acting
factors. In contrast to direct trans-activation and
repression, the corticosteroid receptor does not need to physically
bind DNA in the latter cases, although this mechanism does impinge on
gene expression. The relevance of these mechanisms of action to
aldosterone signaling is considered below.
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Trans-activation. Both MR and GR modulate gene expression through the canonical pentadecamer SRE, with the monomers of the dimeric receptor complex binding each "half-site" (hSRE). The finding that MR and GR have distinct effects on cognition and learning mediated by the hippocampus supports the possibility of unique MR and GR cis-acting elements or that unique protein-protein interactions involving these distinct receptors convey different signals (43, 44). MR and GR also have distinguishable actions in the colon (9, 27, 39, 181). Further support for unique cis-acting elements comes from the study of model systems. In one model system, MR has only 5% of the trans-acting activity of GR on the mouse mammary tumor virus promotor in CV-1 cells (4, 140). However, these results may just as easily reflect findings that trans-activation in response to MR and GR is ligand dependent and influenced differentially by numerous accessory factors (51, 137). The most direct support for MR and GR serving distinct functions comes from mice genetically engineered to be devoid of one receptor type or the other or to express a receptor mutant with a partial loss of function (16, 17, 40, 72, 78, 134; see Trans-repression). From these animals, it is clear that GR influences lung maturation, response to stress, metabolism, and inflammation as well as immune responses. MR, on the other hand, primarily mediates a mineralocorticoid response in epithelia to maintain electrolyte and fluid balance.
The cis-acting elements responsive to corticosteroid receptors for many aldosterone-induced genes have now been identified. A corticosteroid-sensitive gene encodes serum and glucocorticoid-inducible kinase (Sgk; 36, 45, 104, 186, 187). Presently, three isoforms of Sgk (Sgk1, Sgk2, and Sgk3) are recognized, of which only Sgk1 is corticosteroid sensitive (reviewed in Ref. 124). Thus, for simplicity, Sgk1 is referred to as Sgk. The promotor region of the sgk gene contains a classic but imperfect pentadecameric cis-acting SRE (AGGACAgaaTGTTCT; 104, 187). In mammary epithelia, this element is trans-activated in response to dexamethasone signaling (104, 187). Indirect evidence from numerous epithelia, including the renal distal nephron and distal colon, infers that this cis-element is also responsive to aldosterone via MR (18, 28, 36, 45, 101, 151). That glucocorticoids and aldosterone via GR and MR trans-activate sgk in distinct tissues through a common SRE suggests that both types of steroids may initiate a cellular response mediated by a common signaling pathway or one that contains many common signaling elements. Thus GR and MR likely have, at least partially, overlapping functions in epithelia expressing both receptors. This possibility, however, remains quite controversial. Functional redundancy is supported, nevertheless, by findings showing that aldosterone via MR and glucocorticoids via GR induce expression of many of the same genes and that the widely expressed GR is sometimes capable of complementing MR dysfunction or eliciting a mineralocorticoid response, especially in disease states (22, 37, 53, 58, 75, 97, 137). A corticosteroid-sensitive gene also encodes theTrans-repression. Glucocorticoids via GR repress expression of a host of genes. Recent studies also have identified several aldosterone-repressed genes and proteins (92, 135, 154). Compared with induction, less is known about the molecular mechanisms of direct gene repression in response to corticosteroids. Almost nothing is known about MR-mediated repression, including a complete paucity of information regarding cis-acting elements and accessory proteins involved in this action. The term "negative"-SRE (nSRE) is used here to define the cis-acting element that directly mediates trans-repression in response to glucocorticoid signaling via GR.
GR interacts directly with the 5'-ATTTTTGTCAATGGACAAGTCATAAGAA-3' nSRE sequence in the promotor region of the corticotropin-releasing hormone gene to trans-repress cAMP-activated expression of this gene (105, 106). A cis-acting element in the promotor of the prolactin gene that is bound by ligand-activated GR also has been identified (141). This element exerts positive tonic regulation of prolactin and heterologous promotors in the absence of liganded GR. Tonic regulation is suppressed in the presence of ligand-activated GR. In a study involving both in vivo and in vitro work, Burke and colleagues (30) mapped the cis-acting element bound by GR during trans-repression of the bovine vasopressin gene. The nSRE in the gene encoding proopiomelanocortin (POMC; 5'-GGAAGGTCACGTCCA-3') has also been identified (35, 48, 49). Compared with SRE involved in trans-activation, which bind GR dimers, the nSRE in POMC simultaneously binds a GR homodimer and monomer in a cooperative manner. It is not presently known how the novel arrangement of three GR around this nSRE affects transcription machinery and other factors to repress expression. The effects of MR on these nSREs have not been studied, and thus it remains to be determined whether MR is capable of modulating expression via these sorts of nSREs. As of the writing of this review, no nSRE definitively responsive to MR has been reported, and it is unclear whether one actually exists. The recent identification of a number of putative aldosterone-repressed genes and proteins (92, 135, 154) points to possible candidates worthy of further investigation in this regard. Another consideration worthy of further study is that gene repression in response to aldosterone does not directly involve binding to nSRE. This alternative mechanism could take one of two forms: 1) a secondary response dependent on the primary induction of factors that ultimately negatively influence transcription of the repressed genes and 2) a response dependent on protein-protein interactions between MR and other accessory or transcription factors that then negatively influence expression without MR actually binding DNA. It has become apparent in the last couple of years that many genes repressed by glucocorticoids in fact do not contain an nSRE directly bound by ligand-activated GR. It is accepted that these genes are repressed by direct protein-protein interactions between ligand-activated GR and other trans-acting factors, which bind DNA in the promotor region of the repressed genes. Indeed, it is now believed that most corticosteroid gene repression actually results from a molecular mechanism involving transcription interference mediated by protein-protein interactions and not direct trans-repression of expression (reviewed in Ref. 78). Also being reevaluated is whether such protein-protein interactions actually play a more prominent role in trans-activation than was initially thought (134).Protein-protein interactions during MR and GR modulation of gene
expression.
The -casein gene is induced by GR independently of SRE
(163). The mechanism of action here entails GR
"tethering" through a protein-protein interaction to signal
transducer and activator of transcription-5 (Stat-5), with the latter
factor associating with its respective cis-element in the
promotor region of the
-casein gene (see Fig. 1). Induction of
-casein in response to glucocorticoids, then, is actually dependent
on formation of GR-Stat-5 heterodimers that bind to Stat-5 response
elements without ligand-activated GR actually interacting with its
cognate DNA-binding site. GR forms an equivalent type of complex with
the transcription factor organic cation transporter-2
(130) and has also been reported to associate with Stat-3
(200). It is not known whether MR also binds these and/or
other such tethering factors, and thus such a mechanism of action
involving transcription synergy for MR is purely speculative at this
time. If MR has limited interaction with these tethering factors or
interacts with distinct ones, this mechanism might then distinguish
between GR and MR responses.
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ALDOSTERONE-INDUCED PROTEINS |
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Significant advances clearly have been made in the last couple of years in identifying aldosterone-induced transcripts and proteins, as well as in determining the molecular mechanism for modulation of aldosterone-sensitive genes. Similarly, our general understanding of the function of aldosterone-induced proteins during a mineralocorticoid response is also becoming clearer. However, much remains to be learned about the mechanism by which aldosterone-induced proteins exert their final control over cellular activity. This is particularly evident when one considers that very little detailed information exists about how aldosterone-induced proteins specifically interact and regulate their respective effectors in epithelia. Our understanding of the cellular signaling cascade transducing the actions of aldosterone at the nucleus outward toward the plasma membrane, where its final effectors are located, is also very limited. These areas of aldosterone signaling are the primary focus of most contemporary research investigating the mineralocorticoid response.
Temporal Actions of Aldosterone
The genomic actions of aldosterone are traditionally divided into an early and late phase (reviewed in Refs. 176-178). This division is somewhat arbitrary, and it is unclear whether and/or how the two phases are related. Moreover, the physiological significance of each discrete phase has never been definitively quantified. However, it has been suggested that the later phase of aldosterone action sets the capacity of transport epithelia for solute and water (re)absorption, and thus this phase may be considered a trophic or chronic response (159, 176, 178). At a superficial level, the genes affected by aldosterone during the later phase, those encoding transport proteins and proteins involved in energy metabolism for example, appear to support this contention. The early phase, in comparison, is predicted to respond to acute changes in salt and water balance to allow for more rapid responses to movements away from homeostasis. That aldosterone primarily affects transcription of signaling factors, such as Sgk and Ki-Ras, during the early phase is consistent with such a mechanism. Because the in vivo effects of aldosterone have been almost exclusively studied at extremes, little information exists regarding dose-dependent actions and threshold effects during either phase in the integrated system. In addition, the significance of time-dependent aldosterone responses in whole animal studies is often obscured by experimental limitations.The early phase of aldosterone action is most often demarcated as the period where Na+ transport is increased without an accompanying increase in the levels of the transport proteins involved in this action. This phase directly follows the 0.5- to 1.0-h latent period required for changes in gene expression and proceeds for 2-4 h. The second phase, then, is classified as that following this period and is associated with a further or sustained increase in transport accompanied by increases in the number of transport proteins, such as ENaC and the Na+/K+-ATPase (reviewed in Refs. 52 and 176-178). Both phases clearly have an absolute requirement on induction/repression of gene expression. For the early phase, aldosterone action is considered to be exclusively mediated through a primary effect on gene expression. In contrast, the later phase results from both primary and secondary effects on gene expression. Both phases also involve regulation at the level of posttranslation. The distinction between these phases demonstrates that aldosterone induces signaling proteins during the early phase that result in activation via posttranslational control of existing proteins involved in transport. These early signaling factors potentially could also lead into the later phase by stimulating a second round of gene expression to increase production and guarantee proper regulation of transport proteins.
Early actions of aldosterone. The initial actions of aldosterone with respect to increasing Na+ (re)absorption and K+ secretion are mediated by existing transport proteins that are targeted by diffusible signaling factors, the expression of which is regulated at the level of transcription by steroids. The limiting step in both transcellular Na+ and K+ movement are the activities of the apical ion channels mediating (re)absorption and secretion, respectively. Although the serosal Na+/K+-ATPase is essential to the maintenance of the electrochemical forces necessary for transport, there is enough inherent capacity within pump number and activity to ensure a constant gradient favoring Na+ (re)absorption and K+ secretion (reviewed in Refs. 52, 60, and 176). Thus the activity of the Na+/K+-ATPase is not typically considered to be limiting during the early phase of aldosterone action. Considering this, then, there are ultimately only two ways aldosterone can enhance transport: 1) by increasing the open probability of apical ion channels and 2) by increasing the number of active ion channels in the luminal membrane. There is considerable and often conflicting evidence supporting both mechanisms of action (47, 56, 59, 67, 73, 80, 84, 85, 189). Importantly, an aldosterone-induced change in channel-gating kinetics and number during the early phase of action is not necessarily mutually exclusive. In fact, as described below, Sgk is presently believed to increase ENaC number in the apical membrane, whereas Ki-RasA is believed to influence channel gating, with both happening during the early phase.
Late actions of aldosterone.
The late actions of aldosterone are primarily trophic. During this
phase, there is a clear increase in the amount of ENaC protein within
the cell, as well as at the apical membrane (100, 107,
189). However, controversy surrounds which subunits of the
heteromultimeric ENaC are induced by aldosterone, with some studies
showing increases in -ENaC levels (100, 107, 110, 114)
and some increases in
-ENaC levels (158, 189), and yet others reporting increases in both (42, 47). Moreover,
controversy surrounds the idea that expression and insertion into the
apical membrane of ENaC subunits are discordantly and independently
regulated by aldosterone (67, 100, 107, 139, 189). Similar
to ENaC, the number of Na+/K+-ATPase pumps and
of the secretory, apical K+ channel (ROMK) increase in
response to steroids (180). Indeed, aldosterone
definitively induces, at the level of transcription, expression of the
gene encoding the
1- and possibly
1-subunits of the Na+/K+-ATPase
(24, 88, 89), as well as inducing expression of corticosteroid hormone-induced factor (CHIF; see below), a protein that
shares much similarity with the
-subunit of the
Na+/K+-ATPase. In addition to increases in
these transport proteins, enzymes essential to energy metabolism
increase (52, 176, 178). All three actions combine to
establish a cell programmed for prolonged ion transport. Thus the
programming associated with the trophic action of aldosterone could in
a general sense be considered further differentiation of these
epithelial cells. It is provocative, as described further below, that
many of the early signals of aldosterone are also associated with
cellular growth and differentiation.
Function of Aldosterone-Induced/Regulated Proteins
As described above, aldosterone influences expression of a broad pool of genes, and its actions are pleiotropic, involving regulation of several distinct end-effectors through the amalgamation of diverse intermediaries and signaling inputs. A definitive understanding of the roles played by most aldosterone-induced proteins is presently lacking; however, it is accepted that aldosterone signaling is quite complex with much convergence and divergence onto key signaling factors that program the intended cellular response. The two signaling factors induced by aldosterone that have recently garnered much attention as key mediators in a mineralocorticoid response are Sgk and Ki-RasA.2 Figure 2 shows a working model of aldosterone signaling that includes some of the known aldosterone-induced proteins and their activators and effectors.
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Function of Sgk. Of the recently identified aldosterone-induced genes, sgk has received the most attention (reviewed in Refs. 120, 124, and 125). This gene was established originally in fibroblasts and mammary epithelia as an immediate-early gene induced by glucocorticoids at the level of transcription independently of de novo protein synthesis (186, 187). Subsequently, the Pearce (36) and Naray-Fejes-Toth (119) laboratories simultaneously identified sgk as a primary aldosterone-induced gene in amphibian and mammalian renal epithelia. This transcript also is strongly induced by corticosteroids throughout the gastrointestinal tract but not the lungs (28, 151). From these findings, it is clear that a more complete understanding of how corticosteroids target induction of sgk in kidney and gut but not lung will yield insight into the cellular/molecular mechanisms bestowing steroid specificity. The sgk transcript is also commonly expressed in many nonepithelial tissues in a corticosteroid-insensitive manner, suggesting that some sgk expression must be constitutive (36, 187). Corticosteroids, through both GR and MR, increase sgk levels within 15-30 min of treatment, with levels peaking after 1-2 h and subsequently tending to pretreatment values soon afterward. Induction by aldosterone of Sgk protein in renal epithelia follows a similar time course, with protein levels increasing within 30 min, peaking by 6 h, and returning to pretreatment levels by 24 h (36).
Sgk is a serine/threonine kinase that shares much homology with protein kinase B (PKB)/Akt kinases and phosphorylates at a consensus sequence (RXRXXS/T; optimal site KKRNRRLSVA) similar to that targeted by PKB/Akt, protein kinase C, and p90 ribosomal protein S6 kinase (86, 122). Sgk itself is a phosphoprotein, with phosphorylation by PDK-1 being required for Sgk activity (86, 122). Interestingly, aldosterone increases both absolute and phospho-Sgk levels in renal A6 cells (185), suggesting that, in addition to inducing sgk expression, aldosterone activates a converging signaling cascade that ensures proper phosphorylation of Sgk. The lipid/protein kinase PI3K is upstream of PDK-1 in the PI3K signaling cascade and is required for activation of PDK-1 and, subsequently, Sgk, by insulin, insulin-like growth factor (IGF)-1, and other stimuli (122). Thus Sgk is a constituent of the PI3K signaling cascade positioned downstream of PDK-1 in parallel with PKB/Akt (77, 86, 175). In renal A6 epithelia, inhibition of PI3K attenuates aldosterone-induced increases in Na+ transport and in the active (phosphorylated) but not absolute levels of Sgk (185). This maneuver also blocks activation of Sgk and Na+ transport by insulin in the same cells. These observations are consistent with aldosterone-stimulating Sgk activation by control of sgk transcription and posttranslational modification. It is exciting that, in A6 cells, aldosterone stimulates PI3K activity independently of inducing PI3K expression (20, 21) and induces expression of Ki-RasA (154, 161), which is an upstream activator of PI3K (55, 192). Thus, as discussed further in this and the subsequent subsection, two primary aldosterone-induced genes encode signaling factors Sgk and Ki-RasA, which belong to a converging signaling cascade. Also exciting are results from a recent proteomic analysis of A6 cells treated with aldosterone that identified theFunction of Ki-RasA. The small, monomeric GTP-binding protein Ki-RasA, like Sgk, is encoded by an aldosterone-induced transcript and plays a pivotal role in mediating aldosterone action in renal epithelia. Spindler and colleagues (154) were the first to identify Ki-ras as an aldosterone-induced gene. In particular, this group identified the A splice variant of Ki-ras as sensitive to aldosterone. There are four homologous Ras proteins: Ha-Ras, N-Ras, Ki-RasA, and Ki-RasB. The latter two result from splice variants encoded by a common gene (reviewed in Ref. 8). Induction of Ki-rasA is a primary action of aldosterone that is independent of de novo protein synthesis. Previously, the Shekhar (127, 149) and Pelling laboratories (121, 165) showed that both the Ha-ras and Ki-ras genes were induced by glucocorticoids. It is unclear why aldosterone does not induce Ha-ras expression in epithelia capable of vectorial Na+ (re)absorption, but this appears to be a common finding among investigators studying aldosterone action (1, 154, 161; Stockand JD, unpublished observations; Fuller P, personal communication). Further study of this apparent controversy may shed light on aldosterone/glucocorticoid and MR/GR specificity. Subsequent to the initial study by Spindler and colleagues (154), Stockand et al. (161) and Spindler et al. (155) showed that aldosterone increased Ki-RasA protein levels. Aldosterone induces Ki-RasA during the early phase of action, with levels rising as early as 30 min after treatment. Controversy has surrounded the importance of Ki-RasA to aldosterone signaling. This controversy centers on concerns that aldosterone-dependent induction of Ki-rasA does not appear common to all epithelia capable of a mineralocorticoid response. Aldosterone via MR preferentially increases Ki-RasA transcript and protein levels in amphibian distal nephron (155), rodent colon (Fuller P, personal communication) and heart (Stockand JD and Meszaros JG, unpublished observations) and via GR in amphibian renal A6 cells (154, 161). Corticosteroids via GR, in addition, increase Ha-ras and Ki-ras levels in epidermal (165) and mammary epithelia (127, 149). In contrast to these findings, the Brown (131) and Verrey laboratories (personal communication) have been unable to detect the effects of aldosterone on Ki-ras in mouse and rat kidney. Robert-Nicoud and colleagues (135), using a distinctly molecular strategy, were also unable to identify sgk and Ki-ras as being induced by aldosterone in a collecting duct cell line. As pointed out by this group, such negative findings likely reflect, in part, the low expression levels of these transcripts in differentiated cells, which make them difficult to identify much less quantify. Resolution of this apparent conflict, however, is essential for distinguishing whether Ki-RasA plays a fundamental and universal role in aldosterone signaling or whether it is critical to steroid signaling only in select tissues and particular species. Nonetheless, in cells where aldosterone does increase Ki-RasA, this protein plays an important role in mediating the mineralocorticoid response.
Mastroberardino and colleagues (109) showed in the heterologous X. laevis oocyte expression system that overexpression of constitutively active Ki-RasA with ENaC has conflicting actions on the ion channel, both stabilizing the open probability and decreasing the number of channels in the plasma membrane. The effect on channel number resulted from nonspecific actions of activated Ki-RasA on induction of oocyte maturation. Although exciting, interpretation of these results was somewhat limited for they were performed in a heterologous system utilizing a nonpolarized, nonepithelial cell type not responsive to aldosterone or capable of regulated solute transport, and only after chronic overexpression of both ENaC and activated Ki-RasA proteins. We demonstrated in a subsequent study that induction of Ki-RasA during the early phase is necessary and sufficient for some part of aldosterone's action on Na+ transport in polarized renal A6 epithelial cells (161). In this study, as well as in a follow-up study (1), Ras was shown to be critical for stabilization of ENaC in the open state. The molecular mechanism by which Ras does this remains elusive. Indirect evidence from several other studies (11, 162), however, suggests that Ras must be in close proximity to ENaC and that the Ras-to-ENaC signal mediating changes in gating kinetics is, at least partially, membrane delimited (reviewed in Ref. 159). Thus direct interaction between Ras and ENaC leading to channel stabilization is not unexpected. Alternatively, Ras could signal to ENaC through effector proteins that are also localized to the plasma membrane. Although aldosterone-induced Ki-RasA clearly affects ENaC gating during the early phase of action, its action on channel number is less clear, but Ras signaling is known to activate PI3K in numerous cell types (55, 138, 192) and possibly Sgk in A6 epithelia (160), both of which affect ENaC number (20, 21, 123, 124). During states of chronic and unrestricted activation of Ras and its downstream effector cascades, specifically the MAPK cascade, ENaC levels are ultimately decreased in both native epithelia and heterologous systems (98, 109, 184, 198). Aldosterone likely does more than just increase Ki-RasA levels. In addition, Ki-RasA activates several distinct effector cascades, including the MAPK and PI3K cascades, which differentially affect ENaC (21, 98, 123, 185, 198). Thus the decrease in ENaC levels resulting from prolonged and unrestricted activation of Ras and MAPK signaling not unexpectedly may reveal a potential, classic negative-feedback pathway that could temper avid Na+ reabsorption in the continued presence of aldosterone. Preliminary results presented in abstract form (160) indeed demonstrate that MAPK signaling downstream of Ki-RasA does not play a role in the positive actions of aldosterone but that Ras-dependent PI3K signaling does. As noted above, Ras and MAPK signaling decreaseFunction of PI3K during an aldosterone and insulin response. PI3K, a multimeric enzyme containing both catalytic and regulatory subunits, is important to both aldosterone- and insulin-dependent actions on epithelia (20, 21, 123, 133). However, PI3K is not an aldosterone-induced protein, but its activity is increased by both aldosterone and insulin in renal epithelial cells. Blockade of PI3K impedes both the early and late phases of aldosterone actions, with PI3K apparently promoting/protecting ENaC levels in the apical membrane. Similar effects are observed when PI3K is inhibited during insulin induction of Na+ transport. Thus PI3K is either permissive for Na+ transport or it is common to both the aldosterone- and insulin-signaling pathways that culminate in increased Na+ transport (see Fig. 2). If the latter scenario is true, then PI3K activity must be directly and continuously linked to ENaC activity for, when this kinase is inhibited, sustained Na+ transport is quickly diminished even in the continued presence of aldosterone and insulin. This observation, in conjunction with those showing that aldosterone-sensitive Sgk levels rise within 1-2 h and then return by 4-6 h to pretreatment levels in the continued presence of aldosterone (see above), seems to indicate that PI3K plays a role in addition to that of activating Sgk during chronic aldosterone signaling. At this time, the Sgk-independent role for PI3K is unclear. It is possible, however, that some epithelia have enough basal Sgk1 and/or Sgk2 and -3 expression to enable constant PI3K signaling to ENaC through this pathway.
In contrast to aldosterone, which results in an increase in transport only after a latent period required for gene expression, insulin quickly (within minutes) stimulates transport independently of gene modulation, utilizing a signaling cascade that is initiated at the plasma membrane. Insulin is recognized to stimulate PI3K through a transduction pathway involving several adapter proteins that ultimately couple PI3K activity to allosteric changes in the insulin receptor. How aldosterone induces PI3K activity and where this kinase fits into the aldosterone transduction pathway remain less clear. One possibility that is consistent with all present findings is that aldosterone-dependent induction of Ki-RasA leads to activation of PI3K (see Fig. 2). PI3K is a well-known first effector of Ras proteins, including Ki-RasA (55, 192). With such mechanisms of PI3K activation, insulin would quickly affect the kinase, whereas aldosterone would only affect the kinase after the latent period required for Ki-RasA transcription and translation. In addition to aldosterone and insulin, vasopressin has been reported to stimulate Na+ transport in A6 cells through a mechanism dependent, in part, on PI3K (50). Thus PI3K may be a focal point where insulin, vasopressin, and aldosterone signal transduction converge to activate a common cascade directed toward ENaC and/or the Na+/K+-ATPase.Function of CHIF. CHIF was first identified as a corticosteroid-induced gene in rat colon (6). CHIF is expressed in epithelia of the distal colon and nephron (6, 33, 181). This protein is localized primarily to the basolateral membrane, where it presumably interacts with its final effector to stimulate transport (150). Corticosteroids via MR but not GR regulate CHIF expression at the level of transcription in colon but not kidney (27, 33, 181, 182). Induction of CHIF in the colon in response to corticosteroids is a primary action independent of de novo protein synthesis, with CHIF levels increasing as early as 1 h after steroid treatment (27). In contrast to the colon, in the kidney, CHIF expression is modulated by aldosterone at the level of translation and/or posttranslation (150). Thus CHIF expression must be regulated differently by aldosterone in the colon and kidney. How aldosterone modulates CHIF translation in the kidney remains a mystery, but identification of the cis-acting element and molecular mechanism regulating CHIF expression in the colon is excitedly awaited. Because this element is responsive to MR but not GR, identifying it in the gut will likely yield great insight into the mechanisms defining corticosteroid hormone receptor specificity.
CHIF is a member of the newly identified FXYD protein family as defined by Sweadner and Rael (167). CHIF, similar to other FXYD proteins, is a transmembrane regulator of ion channels and other transport proteins (6, 147). TheFunction of glucocorticoid-induced leucine zipper protein.
Robert-Nicoud et al. (135), using serial analysis of gene
expression, identified in an immortalized mouse principal cell line,
which contains MR, the glucocorticoid-induced leucine zipper protein
(GILZ) as being encoded by an aldosterone-induced gene (135). GILZ transcript levels were increased by
aldosterone within 30 min, indicating that it is an early signal. GILZ
belongs to the transforming growth factor--stimulated clone 22 (TSC-22)/DSIP-immunoreactive leucine zipper protein/bunched
(TSC-22/DIP/bun) family of proteins originally thought to be
transcription factors but recently reconsidered to serve an as yet
undetermined function. How GILZ could affect proteins involved
in transport remains unclear; however, it is becoming clear that
leucine zippers, in addition to affecting transcription, are also
capable of modulating ion channel activity in a dynamic manner
(reviewed in Ref. 102). While serving this function,
leucine zippers act as adapter proteins to recruit kinases and
phosphatases into a macromolecular complex with the regulated ion
channel. Interestingly, using a distinct genomics approach, we also
identified TSC-22 with two different probes as being encoded by a
corticosteroid-induced transcript in the M-1 cell line that is
increased within 3 h of steroid treatment (Stockand JD and Eaton
DC, unpublished observations).
Function of Aldosterone-Induced Transport Proteins
As discussed above (see Late actions of aldosterone), aldosterone induces expression of ENaC, ROMK, and the Na+/K+-ATPase pump at the level of transcription, with this induction being part of the trophic, late actions of aldosterone. The functional consequences of these effects of aldosterone with respect to a mineralocorticoid response are straightforward. In addition to these transport proteins, aldosterone induces expression of the luminal Na+/H+ exchanger (NHE3) in the proximal but not distal portion of the colon (39) and the luminal, thiazide-sensitive Na+-Cl ![]() |
AN INTEGRATED MODEL |
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It is hard to overlook the fact that there is possibly a linear
signaling relationship between aldosterone-induced Ki-RasA and Sgk,
with PI3K positioned between these factors. In addition, other
corticosteroid-regulated proteins, such as PP2A and A-Raf, potentially influence or are influenced by these factors. When the
common nature of these factors to signaling cascades that control
cellular growth, apoptosis and differentiation is considered, one generalized view of the actions of aldosterone on epithelia is that
this steroid programs the cell to "differentiate" more toward a
Na+-reabsorbing state and that Ki-RasA and Sgk are merely
the early messengers of this signal. Adding further support for such a
generalized mechanism is that corticosteroids, via the initiation of a
complex interaction between Ras and PI3K signaling, are known to induce functional polarity and promote formation of tight junctions and transepithelial resistances in mammary epithelia (32,
190). Moreover, signaling through MR promotes differentiation of
brown adipocytes (126), and PI3K is a central switch
directing tubulogenesis of epithelial cells (82). This
generalized cascade would contain multiple converging and diverging
pathways, exerting pleiotropic effects on epithelia. Shown in Fig. 2 is
one possible signaling cascade that includes many of the known
aldosterone-regulated proteins. What is clear in this idealized cascade
are the many sites for possible cross talk and feedback. For instance,
Ki-RasA can activate PI3K, which in turn can activate PDK1, which then activates Sgk. Ki-RasA also activates the MAPK cascade via stimulation of Raf. Active Sgk is a negative regulator of B-Raf through
phosphorylation (199). Could Sgk possibly also regulate
the corticosteroid-induced gene A-Raf and other Raf proteins, such as
c-Raf, that are known effectors of aldosterone-induced Ki-RasA?
PKB/Akt, which shares much homology with Sgk, phosphorylates a similar
consensus site and is positioned at the same site as Sgk in the PI3K
signaling cascade, inhibits both B- and c-Raf via phosphorylation
(66, 77, 138, 202). An additional site of possible cross
talk regulation is between MAPK and Sgk, for MAPK signaling in response
to stimulation of Raf induces expression of sgk in
fibroblasts (116). Here again is a possible
positive-feedback signal with aldosterone-induced Ki-RasA activating
Raf and the MAPK cascade to further ensure sgk expression,
which subsequently directs Ki-RasA signaling to the PI3K cascade by
Akt-mediated inactivation of Raf. Thus Sgk expression and
proper phosphorylation could, in part, be influenced by Ki-RasA
signaling. Numerous other points of possible cross talk exist in this
cascade. For instance, aldosterone-induced Ki-RasA via MAPK signaling
has been shown in A6 cells to lead to induction of MAPK phosphatase-1
(MKP-1) (160), which is a negative-feedback regulator of
MAPK. Indeed, activation of MKP-1 directs Ras
Raf signaling to
cascades other than the MAPK cascade (148). MAPK, in
addition, is a negative regulator of the GTP exchange factors, such as
SOS, that stimulate Ras activity (25, 26, 55).
Interestingly, PI3K via PDK-1 on the other hand, positively influences
GTP exchange factors to prolong Ras signaling (46, 132).
Thus, if all of these points of cross talk hold true in
corticosteroid-sensitive epithelia, then aldosterone induction of
Ki-RasA simultaneously with Sgk would preferentially lead to Ras
PI3K
Sgk signaling with inhibited MAPK signaling. Such a system of transduction is consistent with all the present literature describing the positive actions of Sgk and Ki-RasA, as well as the
negative actions of prolonged MAPK signaling on transport.
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ACKNOWLEDGEMENTS |
---|
Drs. A. Firulli, K. Hamilton, and R. T. Worrell are recognized for critical evaluation of this article.
![]() |
FOOTNOTES |
---|
1 The diseases include, in part, Cushing's syndrome; Conn's syndrome; Addison's disease; hypertension; syndrome of apparent mineralocorticoid excess; Liddle's syndrome; glucocorticoid-remediable aldosteronism; pseudohypoaldosteronism; Gordon's syndrome; some forms of familial hypertension exacerbated by pregnancy; and Gitelman's syndrome (68, 97).
2 Many earlier studies identified aldosterone-induced (and -repressed) proteins using conventional biochemical means. The relationship of the proteins to a mineralocorticoid response and aldosterone effectors has not been clearly established and thus is not discussed here.
Address for reprint requests and other correspondence: J. D. Stockand, Dept. of Physiology, University of Texas Health Science Center at San Antonio, MC-7756, 7703 Floyd Curl Dr., San Antionio, TX 78229-3900 (E-mail: stockand{at}uthscsa.edu).
10.1152/ajprenal.00320.2001
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Al-Baldawi, NF,
Stockand JD,
Al-Khalili OK,
Yue G,
and
Eaton DC.
Aldosterone induces Ras methylation in A6 epithelia.
Am J Physiol Cell Physiol
279:
C429-C439,
2000
2.
Alliston, TN,
Gonzalez-Robayna IJ,
Buse P,
Firestone GL,
and
Richards JS.
Expression and localization of serum/glucocorticoid-induced kinase in the rat ovary: relation to follicular growth and differentiation.
Endocrinology
141:
385-395,
2000
3.
Ankenbauer, W,
Strahle U,
and
Schutz G.
Synergistic action of glucocorticoid and estradiol responsive elements.
Proc Natl Acad Sci USA
85:
7526-7530,
1988[Abstract].
4.
Arriza, JL,
Simerly RB,
Swanson LW,
and
Evans RM.
The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response.
Neuron
1:
887-900,
1988[ISI][Medline].
5.
Arystarkhova, E,
Wetzel RK,
Asinovski NK,
and
Sweadner KJ.
The gamma subunit modulates Na(+) and K(+) affinity of the renal Na,K-ATPase.
J Biol Chem
274:
33183-33185,
1999
6.
Attali, B,
Latter H,
Rachamim N,
and
Garty H.
A corticosteroid-induced gene expressing an "IsK-like" K+ channel activity in Xenopus oocytes.
Proc Natl Acad Sci USA
92:
6092-6096,
1995
7.
Bamberger, CM,
Bamberger AM,
Wald M,
Chrousos GP,
and
Schulte HM.
Inhibition of mineralocorticoid activity by the beta-isoform of the human glucocorticoid receptor.
J Steroid Biochem Mol Biol
60:
43-50,
1997[ISI][Medline].
8.
Bar-Sagi, D.
A Ras by any other name.
Mol Cell Biol
21:
1441-1443,
2001
9.
Bastl, CP,
and
Hayslett JP.
The cellular action of aldosterone in target epithelia.
Kidney Int
42:
250-264,
1992[ISI][Medline].
10.
Baumann, H,
Jahreis GP,
Morella KK,
Won KA,
Pruitt SC,
Jones VE,
and
Prowse KR.
Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB.
J Biol Chem
266:
20390-20399,
1991
11.
Becchetti, A,
Kemendy AE,
Stockand JD,
Sariban- Sohraby S,
and
Eaton DC.
Methylation increases the open probability of ENaC in A6 epithelia.
J Biol Chem
275:
16550-16559,
2000
12.
Beck, FX,
Neuhofer W,
and
Muller E.
Molecular chaperones in the kidney: distribution, putative roles, and regulation.
Am J Physiol Renal Physiol
279:
F203-F215,
2000
13.
Beguin, P,
Crambert G,
Guennoun S,
Garty H,
Horisberger JD,
and
Geering K.
CHIF, a member of the FXYD protein family, is a regulator of Na,K-ATPase distinct from the gamma-subunit.
EMBO J
20:
3993-4002,
2001
14.
Beguin, P,
Wang X,
Firsov D,
Puoti A,
Claeys D,
Horisberger JD,
and
Geering K.
The gamma subunit is a specific component of the Na,K-ATPase and modulates its transport function.
EMBO J
16:
4250-4260,
1997
15.
Benjamin, WB,
and
Singer I.
Aldosterone-induced protein in toad urinary bladder.
Science
186:
269-272,
1974[ISI][Medline].
16.
Berger, S,
Bleich M,
Schmid W,
Cole TJ,
Peters J,
Watanabe H,
Kriz W,
Warth R,
Greger R,
and
Schutz G.
Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism.
Proc Natl Acad Sci USA
95:
9424-9429,
1998
17.
Berger, S,
Bleich M,
Schmid W,
Greger R,
and
Schutz G.
Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism.
Kidney Int
57:
1295-1298,
2000[ISI][Medline].
18.
Bhargava, A,
Fullerton MJ,
Myles K,
Purdy TM,
Funder JW,
Pearce D,
and
Cole TJ.
The serum- and glucocorticoid-induced kinase is a physiological mediator of aldosterone action.
Endocrinology
142:
1587-1594,
2001
19.
Blazer-Yost, B,
Geheb M,
Preston A,
Handler J,
and
Cox M.
Aldosterone-induced proteins in renal epithelia.
Biochim Biophys Acta
719:
158-161,
1982[ISI][Medline].
20.
Blazer-Yost, BL,
Liu X,
and
Helman SI.
Hormonal regulation of ENaCs: insulin and aldosterone.
Am J Physiol Cell Physiol
274:
C1373-C1379,
1998
21.
Blazer-Yost, BL,
Paunescu TG,
Helman SI,
Lee KD,
and
Vlahos CJ.
Phosphoinositide 3-kinase is required for aldosterone-regulated sodium reabsorption.
Am J Physiol Cell Physiol
277:
C531-C536,
1999
22.
Bleich, M,
Warth R,
Schmidt-Hieber M,
Schulz-Baldes A,
Hasselblatt P,
Fisch D,
Berger S,
Kunzelmann K,
Kriz W,
Schutz G,
and
Greger R.
Rescue of the mineralocorticoid receptor knock-out mouse.
Pflügers Arch
438:
245-254,
1999[ISI][Medline].
23.
Bloem, LJ,
Guo C,
and
Pratt JH.
Identification of a splice variant of the rat and human mineralocorticoid receptor genes.
J Steroid Biochem Mol Biol
55:
159-162,
1995[ISI][Medline].
24.
Blot-Chabaud, M,
Djelidi S,
Courtois-Coutry N,
Fay M,
Cluzeaud F,
Hummler E,
and
Farman N.
Coordinate control of Na,K-ATPase mRNA expression by aldosterone, vasopressin and cell sodium delivery in the cortical collecting duct.
Cell Mol Biol
47:
247-253,
2001[ISI].
25.
Bokemeyer, D,
Lindemann M,
and
Kramer HJ.
Regulation of mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle cells.
Hypertension
32:
661-667,
1998
26.
Bokemeyer, D,
Sorokin A,
and
Dunn MJ.
Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells.
J Am Soc Nephrol
8:
40-50,
1997[Abstract].
26a.
Booth, RE,
Johnson JP,
and
Stockand JD.
Aldosterone.
Adv Physiol Educ
26:
6-18,
2002.
27.
Brennan, FE,
and
Fuller PJ.
Acute regulation by corticosteroids of channel-inducing factor gene messenger ribonucleic acid in the distal colon.
Endocrinology
140:
1213-1218,
1999
28.
Brennan, FE,
and
Fuller PJ.
Rapid upregulation of serum and glucocorticoid-regulated kinase (sgk) gene expression by corticosteroids in vivo.
Mol Cell Endocrinol
166:
129-136,
2000[ISI][Medline].
29.
Brunet, A,
Park J,
Tran H,
Hu LS,
Hemmings BA,
and
Greenberg ME.
Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a).
Mol Cell Biol
21:
952-965,
2001
30.
Burke, ZD,
Ho MY,
Morgan H,
Smith M,
Murphy D,
and
Carter D.
Repression of vasopressin gene expression by glucocorticoids in transgenic mice: evidence of a direct mechanism mediated by proximal 5' flanking sequence.
Neuroscience
78:
1177-1185,
1997[ISI][Medline].
31.
Buse, P,
Tran SH,
Luther E,
Phu PT,
Aponte GW,
and
Firestone GL.
Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells.
J Biol Chem
274:
7253-7263,
1999
32.
Buse, P,
Woo PL,
Alexander DB,
Reza A,
and
Firestone GL.
Glucocorticoid-induced functional polarity of growth factor responsiveness regulates tight junction dynamics in transformed mammary epithelial tumor cells.
J Biol Chem
270:
28223-28227,
1995
33.
Capurro, C,
Coutry N,
Bonvalet JP,
Escoubet B,
Garty H,
and
Farman N.
Cellular localization and regulation of CHIF in kidney and colon.
Am J Physiol Cell Physiol
271:
C753-C762,
1996
34.
Cha, HH,
Cram EJ,
Wang EC,
Huang AJ,
Kasler HG,
and
Firestone GL.
Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21waf1/cip1 promoter in rat hepatoma cells.
J Biol Chem
273:
1998-2007,
1998
35.
Charron, J,
and
Drouin J.
Glucocorticoid inhibition of transcription from episomal proopiomelanocortin gene promoter.
Proc Natl Acad Sci USA
83:
8903-8907,
1986[Abstract].
36.
Chen, S,
Bhargava S,
Mastroberardino L,
Meijer OC,
Wang J,
Firestone P,
Verrey F,
and
Pearce D.
Epithelial sodium channel regualted by aldosterone-induced protein sgk.
Proc Nat Acad Sci USA
96:
2514-2519,
1999
37.
Chen, SY,
Wang J,
Liu W,
and
Pearce D.
Aldosterone responsiveness of A6 cells is restored by cloned rat mineralocorticoid receptor.
Am J Physiol Cell Physiol
274:
C39-C46,
1998
38.
Chigaev, A,
Lu G,
Shi H,
Asher C,
Xu R,
Latter H,
Seger R,
Garty H,
and
Reuveny E.
In vitro phosphorylation of COOH termini of the epithelial Na+ channel and its effects on channel activity in Xenopus oocytes.
Am J Physiol Renal Physiol
280:
F1030-F1036,
2001
39.
Cho, JH,
Musch MW,
Bookstein CM,
McSwine RL,
Rabenau K,
and
Chang EB.
Aldosterone stimulates intestinal Na+ absorption in rats by increasing NHE3 expression of the proximal colon.
Am J Physiol Cell Physiol
274:
C586-C594,
1998
40.
Cole, TJ,
Blendy JA,
Monaghan AP,
Krieglstein K,
Schmid W,
Aguzzi A,
Fantuzzi G,
Hummler E,
Unsicker K,
and
Schutz G.
Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.
Genes Dev
9:
1608-1621,
1995[Abstract].
41.
Cram, EJ,
Ramos RA,
Wang EC,
Cha HH,
Nishio Y,
and
Firestone GL.
Role of the CCAAT/enhancer binding protein-alpha transcription factor in the glucocorticoid stimulation of p21waf1/cip1 gene promoter activity in growth-arrested rat hepatoma cells.
J Biol Chem
273:
2008-2014,
1998
42.
Dagenais, A,
Denis C,
Vives MF,
Girouard S,
Masse C,
Nguyen T,
Yamagata T,
Grygorczyk C,
Kothary R,
and
Berthiaume Y.
Modulation of -ENaC and
1-Na+-K+- ATPase by cAMP and dexamethasone in alveolar epithelial cells.
Am J Physiol Lung Cell Mol Physiol
281:
L217-L230,
2001
42a.
Debonneville, C,
Flores SY,
Kamynina E,
Plant PJ,
Tauxe C,
Thomas MA,
Munster C,
Chraibi A,
Pratt JH,
Horisberger JD,
Pearce D,
Loffing J,
and
Staub O.
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.
EMBO J
20:
7052-7059,
2001
43.
De Kloet, ER,
Van Acker SA,
Sibug RM,
Oitzl MS,
Meijer OC,
Rahmouni K,
and
De Jong W.
Brain mineralocorticoid receptors and centrally regulated functions.
Kidney Int
57:
1329-1336,
2000[ISI][Medline].
44.
De Kloet, ER,
Vreugdenhil E,
Oitzl MS,
and
Joels M.
Brain corticosteroid receptor balance in health and disease.
Endocr Rev
19:
269-301,
1998
45.
De La Rosa, DA,
Zhang P,
Naray-Fejes-Toth A,
Fejes-Toth G,
and
Canessa CM.
The serum and glucocorticoid kinase sgk increases the abundance of epithelial sodium channels in the plasma membrane of Xenopus oocytes.
J Biol Chem
274:
37834-37839,
1999
46.
DePaolo, D,
Reusch JE,
Carel K,
Bhuripanyo P,
Leitner JW,
and
Draznin B.
Functional interactions of phosphatidylinositol 3-kinase with GTPase-activating protein in 3T3-L1 adipocytes.
Mol Cell Biol
16:
1450-1457,
1996[Abstract].
47.
Dijkink, L,
Hartog A,
Deen PM,
Van Os CH,
and
Bindels RJ.
Time-dependent regulation by aldosterone of the amiloride-sensitive Na+ channel in rabbit kidney.
Pflügers Arch
438:
354-360,
1999[ISI][Medline].
48.
Drouin, J,
Sun YL,
Chamberland M,
Gauthier Y,
De Lean A,
Nemer M,
and
Schmidt TJ.
Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene.
EMBO J
12:
145-156,
1993[Abstract].
49.
Drouin, J,
Trifiro MA,
Plante RK,
Nemer M,
Eriksson P,
and
Wrange O.
Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription.
Mol Cell Biol
9:
5305-5314,
1989[ISI][Medline].
50.
Edinger, RS,
Rokaw MD,
and
Johnson JP.
Vasopressin stimulates sodium transport in A6 cells via a phosphatidylinositide 3-kinase-dependent pathway.
Am J Physiol Renal Physiol
277:
F575-F579,
1999
51.
Farman, N,
and
Rafestin-Oblin ME.
Multiple aspects of mineralocorticoid selectivity.
Am J Physiol Renal Physiol
280:
F181-F192,
2001
52.
Feraille, E,
and
Doucet A.
Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control.
Physiol Rev
81:
345-418,
2001
53.
Ferrari, P,
and
Krozowski Z.
Role of the 11beta-hydroxysteroid dehydrogenase type 2 in blood pressure regulation.
Kidney Int
57:
1374-1381,
2000[ISI][Medline].
54.
Fisher, KA,
Lee SH,
Walker J,
Dileto-Fang C,
Ginsberg L,
and
Stapleton SR.
Regulation of proximal tubule sodium/hydrogen antiporter with chronic volume contraction.
Am J Physiol Renal Physiol
280:
F922-F926,
2001
55.
Foschi, M,
Chari S,
Dunn MJ,
and
Sorokin A.
Biphasic activation of p21ras by endothelin-1 sequentially activates the ERK cascade and phosphatidylinositol 3-kinase.
EMBO J
16:
6439-6451,
1997
56.
Frindt, G,
Masilamani S,
Knepper MA,
and
Palmer LG.
Activation of epithelial Na channels during short-term Na deprivation.
Am J Physiol Renal Physiol
280:
F112-F118,
2001
57.
Fuller, PJ,
Lim-Tio SS,
and
Brennan FE.
Specificity in mineralocorticoid versus glucocorticoid action.
Kidney Int
57:
1256-1264,
2000[ISI][Medline].
58.
Funder, JW.
Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.
Annu Rev Med
48:
231-240,
1997[ISI][Medline].
59.
Garty, H,
and
Edelman IS.
Amiloride-sensitive trypsinization of apical sodium channels. Analysis of hormonal regulation of sodium transport in toad bladder.
J Gen Physiol
81:
785-803,
1983[Abstract].
60.
Garty, H,
and
Palmer LG.
Epithelial sodium channels: function, structure, and regulation.
Physiol Rev
77:
359-396,
1997
61.
Geheb, M,
Alvis R,
Hercker E,
and
Cox M.
Mineralocorticoid-specificity of aldosterone-induced protein synthesis in giant-toad (Bufo marinus) urinary bladders.
Biochem J
214:
29-35,
1983[ISI][Medline].
62.
Geheb, M,
Alvis R,
Owen A,
Hercker E,
and
Cox M.
Steroid-induced protein synthesis in giant-toad (Bufo marinus) urinary bladders. Correlation with natriferic activity.
Biochem J
218:
221-228,
1984[ISI][Medline].
63.
Geheb, M,
Hercker E,
Singer I,
and
Cox M.
Subcellular localization of aldosterone-induced proteins in toad urinary bladders.
Biochim Biophys Acta
641:
422-426,
1981[ISI][Medline].
64.
Geheb, M,
Huber G,
Hercker E,
and
Cox M.
Aldosterone-induced proteins in toad urinary bladders. Identification and characterization using two-dimensional polyacrylamide gel electrophoresis.
J Biol Chem
256:
11716-11723,
1981
65.
Gonzalez-Robayna, IJ,
Alliston TN,
Buse P,
Firestone GL,
and
Richards JS.
Functional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells.
Mol Endocrinol
13:
1318-1337,
1999
66.
Guan, KL,
Figueroa C,
Brtva TR,
Zhu T,
Taylor J,
Barber TD,
and
Vojtek AB.
Negative regulation of the serine/threonine kinase B-Raf by Akt.
J Biol Chem
275:
27354-27359,
2000
67.
Hager, H,
Kwon TH,
Vinnikova AK,
Masilamani S,
Brooks HL,
Frokiær J,
Knepper MA,
and
Nielsen S.
Immunocytochemical and immunoelectron microscopic localization of -,
-, and
-ENaC in rat kidney.
Am J Physiol Renal Physiol
280:
F1093-F1106,
2001
68.
Hamilton, KL,
and
Butt AG.
The molecular basis of renal tubular transport disorders.
Comp Biochem Physiol A Mol Integr Physiol
126:
305-321,
2000[ISI][Medline].
69.
Hansson, JH,
Schild L,
Lu Y,
Wilson TA,
Gautschi I,
Shimkets R,
Nelson-Williams C,
Rossier BC,
and
Lifton RP.
A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.
Proc Natl Acad Sci USA
92:
11495-11499,
1995[Abstract].
70.
Harvey, BJ,
Condliffe S,
and
Doolan CM.
Sex and salt hormones: rapid effects in epithelia.
News Physiol Sci
16:
174-177,
2001
71.
Hayashi, M,
Tapping RI,
Chao TH,
Lo JF,
King CC,
Yang Y,
and
Lee JD.
BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase.
J Biol Chem
276:
8631-8634,
2001
72.
Heck, S,
Kullmann M,
Gast A,
Ponta H,
Rahmsdorf HJ,
Herrlich P,
and
Cato AC.
A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1.
EMBO J
13:
4087-4095,
1994[Abstract].
73.
Helman, SI,
Liu X,
Baldwin K,
Blazer-Yost BL,
and
Els WJ.
Time-dependent stimulation by aldosterone of blocker-sensitive ENaCs in A6 epithelia.
Am J Physiol Cell Physiol
274:
C947-C957,
1998
74.
Helmberg, A,
Auphan N,
Caelles C,
and
Karin M.
Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor.
EMBO J
14:
452-460,
1995[Abstract].
75.
Holmes, MC,
Kotelevtsev Y,
Mullins JJ,
and
Seckl JR.
Phenotypic analysis of mice bearing targeted deletions of 11beta-hydroxysteroid dehydrogenases 1 and 2 genes.
Mol Cell Endocrinol
171:
15-20,
2001[ISI][Medline].
76.
Hummler, E,
and
Horisberger JD.
Genetic disorders of membrane transport. V. The epithelial sodium channel and its implication in human diseases.
Am J Physiol Gastrointest Liver Physiol
276:
G567-G571,
1999
77.
Jun T, Gjoerup O, and Roberts TM. Tangled Webs:
Evidence of Cross-Talk Between c-Raf-1 and Akt. Online.
http://stke.sciencemag.org/cgi/content/full/OC-sigtrans;1999/13/pe1.
78.
Karin, M.
New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?
Cell
93:
487-490,
1998[ISI][Medline].
79.
Karin, M,
and
Chang L.
AP-1-glucocorticoid receptor crosstalk taken to a higher level.
J Endocrinol
169:
447-451,
2001
80.
Kemendy, AE,
Kleyman TR,
and
Eaton DC.
Aldosterone alters the open probability of amiloride-blockable sodium channels in A6 epithelia.
Am J Physiol Cell Physiol
263:
C825-C837,
1992
81.
Kemppainen, RJ,
and
Behrend EN.
Dexamethasone rapidly induces a novel ras superfamily member-related gene in AtT-20 cells.
J Biol Chem
273:
3129-3131,
1998
82.
Khwaja, A,
Lehmann K,
Marte BM,
and
Downward J.
Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial cells through a novel pathway.
J Biol Chem
273:
18793-18801,
1998
83.
Kim, GH,
Masilamani S,
Turner R,
Mitchell C,
Wade JB,
and
Knepper MA.
The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein.
Proc Natl Acad Sci USA
95:
14552-14557,
1998
84.
Kleyman, TR,
Coupaye-Gerard B,
and
Ernst SA.
Aldosterone does not alter apical cell-surface expression of epithelial Na+ channels in the amphibian cell line A6.
J Biol Chem
267:
9622-9628,
1992
85.
Kleyman, TR,
Zuckerman JB,
Middleton P,
McNulty KA,
Hu B,
Su X,
An B,
Eaton DC,
and
Smith PR.
Cell surface expression and turnover of the -subunit of the epithelial sodium channel.
Am J Physiol Renal Physiol
281:
F213-F221,
2001
86.
Kobayashi, T,
and
Cohen P.
Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.
Biochem J
339:
319-328,
1999[ISI][Medline].
87.
Kolla, V,
and
Litwack G.
Inhibition of mineralocorticoid-mediated transcription by NF-kappaB.
Arch Biochem Biophys
383:
38-45,
2000[ISI][Medline].
88.
Kolla, V,
and
Litwack G.
Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor.
Mol Cell Biochem
204:
35-40,
2000[ISI][Medline].
89.
Kolla, V,
Robertson NM,
and
Litwack G.
Identification of a mineralocorticoid/glucocorticoid response element in the human Na/K ATPase alpha1 gene promoter.
Biochem Biophys Res Commun
266:
5-14,
1999[ISI][Medline].
90.
Kwak, SP,
Patel PD,
Thompson RC,
Akil H,
and
Watson SJ.
5'-Heterogeneity of the mineralocorticoid receptor messenger ribonucleic acid: differential expression and regulation of splice variants within the rat hippocampus.
Endocrinology
133:
2344-2350,
1993[Abstract].
91.
Lang, P,
Gamper N,
Fillon S,
Friedrich B,
Beck S,
Huber S,
Wagner C,
and
Lang F.
Regulation of Voltage Gated K-Channels by the Serum and Glucocorticoid Dependent Kinases Sgk1, 2, 3 (Abstract).
In: Int Union Physiol Sci, 2001, p. 8-30.
92.
Laverty, G,
Bjarnadottir S,
Elbrond VS,
and
Arnason SS.
Aldosterone suppresses expression of an avian colonic sodium-glucose cotransporter.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R1041-R1050,
2001
93.
Le Menuet, D,
Viengchareun S,
Penfornis P,
Walker F,
Zennaro MC,
and
Lombes M.
Targeted oncogenesis reveals a distinct tissue-specific utilization of alternative promoters of the human mineralocorticoid receptor gene in transgenic mice.
J Biol Chem
275:
7878-7886,
2000
94.
Lee, JE,
Beck TW,
Brennscheidt U,
DeGennaro LJ,
and
Rapp UR.
The complete sequence and promoter activity of the human A-raf-1 gene (ARAF1).
Genomics
20:
43-55,
1994[ISI][Medline].
95.
Lee, JE,
Beck TW,
Wojnowski L,
and
Rapp UR.
Regulation of A-raf expression.
Oncogene
12:
1669-1677,
1996[ISI][Medline].
96.
Li, M,
Ye X,
Woodward RN,
Zhu C,
Nichols LA,
and
Holland LJ.
Analysis of the DNA-binding site for Xenopus glucocorticoid receptor accessory factor. Critical nucleotides for binding specificity in vitro and for amplification of steroid-induced fibrinogen gene transcription.
J Biol Chem
273:
9790-9796,
1998
97.
Lifton, RP,
Gharavi AG,
and
Geller DS.
Molecular mechanisms of human hypertension.
Cell
104:
545-556,
2001[ISI][Medline].
98.
Lin, HH,
Zentner MD,
Ho HL,
Kim KJ,
and
Ann DK.
The gene expression of the amiloride-sensitive epithelial sodium channel alpha-subunit is regulated by antagonistic effects between glucocorticoid hormone and ras pathways in salivary epithelial cells.
J Biol Chem
274:
21544-21554,
1999
99.
Liu, W,
Wang J,
Sauter NK,
and
Pearce D.
Steroid receptor heterodimerization demonstrated in vitro and in vivo.
Proc Natl Acad Sci USA
92:
12480-12484,
1995[Abstract].
100.
Loffing, J,
Pietri L,
Aregger F,
Bloch-Faure M,
Ziegler U,
Meneton P,
Rossier BC,
and
Kaissling B.
Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets.
Am J Physiol Renal Physiol
279:
F252-F258,
2000
101.
Loffing, J,
Zecevic M,
Feraille E,
Kaissling B,
Asher C,
Rossier BC,
Firestone GL,
Pearce D,
and
Verrey F.
Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK.
Am J Physiol Renal Physiol
280:
F675-F682,
2001
102.
MacFarlane SN and Levitan IB. Unzipping Ion Channels. Online.
www.stke.org/cgi/content/full/OC_sigtrans; 2001/98/pe1, 1-2.
9-4, 2001.
103.
Magnuson, NS,
Beck T,
Vahidi H,
Hahn H,
Smola U,
and
Rapp UR.
The Raf-1 serine/threonine protein kinase.
Semin Cancer Biol
5:
247-253,
1994[ISI][Medline].
104.
Maiyar, AC,
Phu PT,
Huang AJ,
and
Firestone GL.
Repression of glucocorticoid receptor transactivation and DNA binding of a glucocorticoid response element within the serum/glucocorticoid- inducible protein kinase (sgk) gene promoter by the p53 tumor suppressor protein.
Mol Endocrinol
11:
312-329,
1997
105.
Malkoski, SP,
and
Dorin RI.
Composite glucocorticoid regulation at a functionally defined negative glucocorticoid response element of the human corticotropin-releasing hormone gene.
Mol Endocrinol
13:
1629-1644,
1999
106.
Malkoski, SP,
Handanos CM,
and
Dorin RI.
Localization of a negative glucocorticoid response element of the human corticotropin releasing hormone gene.
Mol Cell Endocrinol
127:
189-199,
1997[ISI][Medline].
107.
Masilamani, S,
Kim GH,
Mitchell C,
Wade JB,
and
Knepper MA.
Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.
J Clin Invest
104:
R19-R23,
1999
108.
Massaad, C,
Houard N,
Lombes M,
and
Barouki R.
Modulation of human mineralocorticoid receptor function by protein kinase A.
Mol Endocrinol
13:
57-65,
1999
109.
Mastroberardino, L,
Spindler B,
Forster I,
Loffing J,
Assandri R,
May A,
and
Verrey F.
Ras pathway activates epithelial Na channel and decreases its surface expression in Xenopus oocytes.
Mol Biol Cell
9:
3417-3427,
1998
110.
May, A,
Puoti A,
Gaeggeler HP,
Horisberger JD,
and
Rossier BC.
Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells.
J Am Soc Nephrol
8:
1813-1822,
1997[Abstract].
111.
McKay, LI,
and
Cidlowski JA.
Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism.
Mol Endocrinol
12:
45-56,
1998
112.
McKay, LI,
and
Cidlowski JA.
Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways.
Endocr Rev
20:
435-459,
1999
113.
McKay, LI,
and
Cidlowski JA.
CBP (CREB binding protein) integrates NF-kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical interactions and antagonism.
Mol Endocrinol
14:
1222-1234,
2000
114.
Mick, VE,
Itani OA,
Loftus RW,
Husted RF,
Schmidt TJ,
and
Thomas CP.
The alpha-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5'-flanking region of the gene.
Mol Endocrinol
15:
575-588,
2001
115.
Mikosz, CA,
Brickley DR,
Sharkey MS,
Moran TW,
and
Conzen SD.
Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1.
J Biol Chem
276:
16649-16654,
2001
116.
Mizuno, H,
and
Nishida E.
The ERK MAP kinase pathway mediates induction of SGK (serum- and glucocorticoid-inducible kinase) by growth factors.
Genes Cells
6:
261-268,
2001
117.
Morin, B,
Woodcock GR,
Nichols LA,
and
Holland LJ.
Heterodimerization between the glucocorticoid receptor and the unrelated DNA-binding protein, Xenopus glucocorticoid receptor accessory factor.
Mol Endocrinol
15:
458-466,
2001
118.
Morin, B,
Zhu C,
Woodcock GR,
Li M,
Woodward RN,
Nichols LA,
and
Holland LJ.
The binding site for Xenopus glucocorticoid receptor accessory factor and a single adjacent half-GRE form an independent glucocorticoid response unit.
Biochemistry
39:
12234-12242,
2000[ISI][Medline].
119.
Naray-Fejes-Toth, A,
Canessa C,
Cleaveland ES,
Aldrich G,
and
Fejes-Toth G.
sgk is an aldosterone-induced kinase in the renal collecting duct.
J Biol Chem
274:
16973-16978,
1999
120.
Naray-Fejes-Toth, A,
and
Fejes-Toth G.
The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates the epithelial sodium channel.
Kidney Int
57:
1290-1294,
2000[ISI][Medline].
121.
Neades, R,
Betz NA,
Sheng XY,
and
Pelling JC.
Transient expression of the cloned mouse c-Ha-ras 5' upstream region in transfected primary SENCAR mouse keratinocytes demonstrates its power as a promoter element.
Mol Carcinog
4:
369-375,
1991[ISI][Medline].
122.
Park, J,
Leong ML,
Buse P,
Maiyar AC,
Firestone GL,
and
Hemmings BA.
Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway.
EMBO J
18:
3024-3033,
1999
123.
Paunescu, TG,
Blazer-Yost BL,
Vlahos CJ,
and
Helman SI.
LY-294002-inhibitable PI 3-kinase and regulation of baseline rates of Na+ transport in A6 epithelia.
Am J Physiol Cell Physiol
279:
C236-C247,
2000
124.
Pearce, D.
The role of SGK1 in hormone-regulated sodium transport.
Trends Endocrinol Metab
12:
341-347,
2001[ISI][Medline].
125.
Pearce, D,
Verrey F,
Chen SY,
Mastroberardino L,
Meijer OC,
Wang J,
and
Bhargava A.
Role of SGK in mineralocorticoid-regulated sodium transport.
Kidney Int
57:
1283-1289,
2000[ISI][Medline].
126.
Penfornis, P,
Viengchareun S,
Le Menuet D,
Cluzeaud F,
Zennaro MC,
and
Lombes M.
The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes.
Am J Physiol Endocrinol Metab
279:
E386-E394,
2000
127.
Pethe, V,
and
Shekhar PV.
Estrogen inducibility of c-Ha-ras transcription in breast cancer cells. Identification of functional estrogen-responsive transcriptional regulatory elements in exon 1/intron 1 of the c-Ha-ras gene.
J Biol Chem
274:
30969-30978,
1999
128.
Pfeiffer, R,
Beron J,
and
Verrey F.
Regulation of Na+ pump function by aldosterone is alpha-subunit isoform specific.
J Physiol (Lond)
516:
647-655,
1999
129.
Pitt, B,
Zannad F,
Remme WJ,
Cody R,
Castaigne A,
Perez A,
Palensky J,
and
Wittes J.
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators.
N Engl J Med
341:
709-717,
1999
130.
Prefontaine, GG,
Lemieux ME,
Giffin W,
Schild-Poulter C,
Pope L,
LaCasse E,
Walker P,
and
Hache RJ.
Recruitment of octamer transcription factors to DNA by glucocorticoid receptor.
Mol Cell Biol
18:
3416-3430,
1998
131.
Ramage, LE,
Christy C,
Seckl JR,
and
Brown RW.
Assessment of 2 candidate aldosterone regulated genes, Sgk and c-KRas-2, in adult kidney and during development (Abstract).
J Endocrinol
164:
293,
2000.
132.
Rameh, LE,
Arvidsson A,
Carraway KL,
Couvillon AD, III,
Rathbun G,
Crompton A,
VanRenterghem B,
Czech MP,
Ravichandran KS,
Burakoff SJ,
Wang DS,
Chen CS,
and
Cantley LC.
A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains.
J Biol Chem
272:
22059-22066,
1997
133.
Record, RD,
Froelich LL,
Vlahos CJ,
and
Blazer-Yost BL.
Phosphatidylinositol 3-kinase activation is required for insulin-stimulated sodium transport in A6 cells.
Am J Physiol Endocrinol Metab
274:
E611-E617,
1998
134.
Reichardt, HM,
Kaestner KH,
Tuckermann J,
Kretz O,
Wessely O,
Bock R,
Gass P,
Schmid W,
Herrlich P,
Angel P,
and
Schutz G.
DNA binding of the glucocorticoid receptor is not essential for survival.
Cell
93:
531-541,
1998[ISI][Medline].
135.
Robert-Nicoud, M,
Flahaut M,
Elalouf JM,
Nicod M,
Salinas M,
Bens M,
Doucet A,
Wincker P,
Artiguenave F,
Horisberger JD,
Vandewalle A,
Rossier BC,
and
Firsov D.
Transcriptome of a mouse kidney cortical collecting duct cell line: effects of aldosterone and vasopressin.
Proc Natl Acad Sci USA
98:
2712-2716,
2001
136.
Roberts, LR,
and
Holland LJ.
Coordinate transcriptional regulation of the three fibrinogen subunit genes by glucocorticoids in cultured primary liver cells from Xenopus laevis.
Endocrinology
132:
2563-2570,
1993[Abstract].
137.
Rogerson, FM,
and
Fuller PJ.
Mineralocorticoid action.
Steroids
65:
61-73,
2000[ISI][Medline].
138.
Rommel, C,
Clarke BA,
Zimmermann S,
Nunez L,
Rossman R,
Reid K,
Moelling K,
Yancopoulos GD,
and
Glass DJ.
Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.
Science
286:
1738-1741,
1999
139.
Rotin, D,
Kanelis V,
and
Schild L.
Trafficking and cell surface stability of ENaC.
Am J Physiol Renal Physiol
281:
F391-F399,
2001
140.
Rupprecht, R,
Arriza JL,
Spengler D,
Reul JM,
Evans RM,
Holsboer F,
and
Damm K.
Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor.
Mol Endocrinol
7:
597-603,
1993[Abstract].
141.
Sakai, DD,
Helms S,
Carlstedt-Duke J,
Gustafsson JA,
Rottman FM,
and
Yamamoto KR.
Hormone-mediated repression: a negative glucocorticoid response element from the bovine prolactin gene.
Genes Dev
2:
1144-1154,
1988[Abstract].
142.
Sayegh, R,
Auerbach SD,
Li X,
Loftus RW,
Husted RF,
Stokes JB,
and
Thomas CP.
Glucocorticoid induction of epithelial sodium channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 5'-flanking region of the human epithelial sodium channel alpha subunit gene.
J Biol Chem
274:
12431-12437,
1999
143.
Schild, L,
Lu Y,
Gautschi I,
Schneeberger E,
Lifton RP,
and
Rossier BC.
Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.
EMBO J
15:
2381-2387,
1996[Abstract].
144.
Schlatter, E,
Lohrmann E,
and
Greger R.
Properties of the potassium conductances of principal cells of rat cortical collecting ducts.
Pflügers Arch
420:
39-45,
1992[ISI][Medline].
145.
Scott, DK,
Mitchell JA,
and
Granner DK.
The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter.
J Biol Chem
271:
31909-31914,
1996
146.
Scott, WN,
and
Sapirsten SV.
Identification of aldosterone-induced proteins in the toad's urinary bladder.
Proc Nat Acad Sci USA
72:
4056-4060,
1975[Abstract].
147.
Sha, Q,
Lansbery KL,
Distefano D,
Mercer RW,
and
Nichols CG.
Heterologous expression of the Na(+),K(+)-ATPase gamma subunit in Xenopus oocytes induces an endogenous, voltage-gated large diameter pore.
J Physiol (Lond)
535:
407-417,
2001
148.
Shapiro, PS,
and
Ahn NG.
Feedback regulation of Raf-1 and mitogen-activated protein kinase (MAP) kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1).
J Biol Chem
273:
1788-1793,
1998
149.
Shekhar, PV,
and
Miller FR.
Correlation of differences in modulation of ras expression with metastatic competence of mouse mammary tumor subpopulations.
Invasion Metastasis
14:
27-37,
1994[ISI][Medline].
150.
Shi, H,
Levy-Holzman R,
Cluzeaud F,
Farman N,
and
Garty H.
Membrane topology and immunolocalization of CHIF in kidney and intestine.
Am J Physiol Renal Physiol
280:
F505-F512,
2001
151.
Shigaev, A,
Asher C,
Latter H,
Garty H,
and
Reuveny E.
Regulation of sgk by aldosterone and its effects on the epithelial Na+ channel.
Am J Physiol Renal Physiol
278:
F613-F619,
2000
152.
Shimkets, RA,
Lifton R,
and
Canessa CM.
In vivo phosphorylation of the epithelial sodium channel.
Proc Natl Acad Sci USA
95:
3301-3305,
1998
153.
Snyder, PM,
Olson DR,
and
Thomas BC.
Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of ENaC.
J Biol Chem
277:
5-8,
2001
154.
Spindler, B,
Mastroberardino L,
Custer M,
and
Verrey F.
Characterization of early aldosterone-induced RNAs identified in A6 kidney epithelia.
Pflügers Arch
434:
323-331,
1997[ISI][Medline].
155.
Spindler, B,
and
Verrey F.
Aldosterone action: induction of p21(ras) and fra-2 and transcription-independent decrease in myc, jun, and fos.
Am J Physiol Cell Physiol
276:
C1154-C1161,
1999
156.
Staub, O,
Abriel H,
Plant P,
Ishikawa T,
Kanelis V,
Saleki R,
Horisberger JD,
Schild L,
and
Rotin D.
Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.
Kidney Int
57:
809-815,
2000[ISI][Medline].
157.
Staub, O,
Gautschi I,
Ishikawa T,
Breitschopf K,
Ciechanover A,
Schild L,
and
Rotin D.
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination.
EMBO J
16:
6325-6336,
1997
158.
Stockand, JD,
Bao HF,
Schenck J,
Malik B,
Middleton P,
Schlanger LE,
and
Eaton DC.
Differential effects of protein kinase C on the levels of epithelial Na channel subunit proteins.
J Biol Chem
275:
25760-25765,
2000
159.
Stockand JD, Edinger R, Eaton DC, and Johnson JP. Toward
understanding the role of methylation in aldosterone-sensitive Na
transport (Abstract). News Physiol Sci 15: 2000.
160.
Stockand, JD,
Johnson JP,
and
Edinger RS.
Aldosterone signaling to the epithelial Na channel (Abstract).
J Am Soc Nephrol
12:
40A,
2001.
161.
Stockand, JD,
Spier BJ,
Worrell RT,
Yue G,
Al-Baldawi N,
and
Eaton DC.
Regulation of Na reabsorption by the aldosterone-induced, small G protein K-Ras2A.
J Biol Chem
274:
35449-35454,
1999
162.
Stockand, JD,
Zeltwanger S,
Bao HF,
Worrell R,
and
Eaton DC.
S-adenosyl-L-homocysteine hydrolase is necessary for aldosterone-induced activity of epithelial Na channels.
Am J Physiol Cell Physiol
281:
C773-C785,
2001
163.
Stoecklin, E,
Wissler M,
Moriggl R,
and
Groner B.
Specific DNA binding of Stat5, but not of glucocorticoid receptor, is required for their functional cooperation in the regulation of gene transcription.
Mol Cell Biol
17:
6708-6716,
1997[Abstract].
164.
Storm, SM,
Cleveland JL,
and
Rapp UR.
Expression of raf family proto-oncogenes in normal mouse tissues.
Oncogene
5:
345-351,
1990[ISI][Medline].
165.
Strawhecker, JM,
Betz NA,
Neades RY,
Houser W,
and
Pelling JC.
Binding of the 97 kDa glucocorticoid receptor to the 5' upstream flanking region of the mouse c-Ha-ras oncogene.
Oncogene
4:
1317-1322,
1989[ISI][Medline].
166.
Sugiyama, T,
Scott DK,
Wang JC,
and
Granner DK.
Structural requirements of the glucocorticoid and retinoic acid response units in the phosphoenolpyruvate carboxykinase gene promoter.
Mol Endocrinol
12:
1487-1498,
1998
167.
Sweadner, KJ,
and
Rael E.
The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression.
Genomics
68:
41-56,
2000[ISI][Medline].
168.
Szerlip, H,
Palevsky P,
Cox M,
and
Blazer-Yost B.
Relationship of the aldosterone-induced protein, GP70, to the conductive Na+ channel.
J Am Soc Nephrol
2:
1108-1114,
1991[Abstract].
169.
Szerlip, HM,
and
Cox M.
Aldosterone-induced glycoproteins: further characterization.
J Steroid Biochem
32:
815-822,
1989[ISI][Medline].
170.
Szerlip, HM,
Weisberg L,
Clayman M,
Neilson E,
Wade JB,
and
Cox M.
Aldosterone-induced proteins: purification and localization of GP65,70.
Am J Physiol Cell Physiol
256:
C865-C872,
1989
171.
Therien, AG,
Karlish SJ,
and
Blostein R.
Expression and functional role of the gamma subunit of the Na, K-ATPase in mammalian cells.
J Biol Chem
274:
12252-12256,
1999
172.
Trapp, T,
Rupprecht R,
Castren M,
Reul JM,
and
Holsboer F.
Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS.
Neuron
13:
1457-1462,
1994[ISI][Medline].
173.
Tu, Y,
and
Wu C.
Cloning, expression and characterization of a novel human Ras-related protein that is regulated by glucocorticoid hormone.
Biochim Biophys Acta
1489:
452-456,
1999[ISI][Medline].
174.
Turnamian, SG,
and
Binder HJ.
Aldosterone and glucocorticoid receptor-specific agonists regulate ion transport in rat proximal colon.
Am J Physiol Gastrointest Liver Physiol
258:
G492-G498,
1990
175.
Vanhaesebroeck, B,
and
Alessi DR.
The PI3K-PDK1 connection: more than just a road to PKB.
Biochem J
346:
561-576,
2000[ISI][Medline].
176.
Verrey, F.
Transcriptional control of sodium transport in tight epithelial by adrenal steroids.
J Membr Biol
144:
93-110,
1995[ISI][Medline].
177.
Verrey, F.
Early aldosterone action: toward filling the gap between transcription and transport.
Am J Physiol Renal Physiol
277:
F319-F327,
1999
178.
Verrey, F,
Pearce D,
Pfeiffer R,
Spindler B,
Mastroberardino L,
Summa V,
and
Zecevic M.
Pleiotropic action of aldosterone in epithelia mediated by transcription and post-transcription mechanisms.
Kidney Int
57:
1277-1282,
2000[ISI][Medline].
179.
Wagner, CA,
Ott M,
Klingel K,
Beck S,
Friedrich B,
Wild KN,
Broer S,
Moschen I,
Albers A,
Waldegger S,
Tummler B,
Egan ME,
Geibel JP,
Kandolf R,
and
Lang F.
Effects of the serine/threonine kinase sgk1 on the epithelial Na(+) channel (eNaC) and CFTR: implications for cystic fibrosis.
Cell Physiol Biochem
11:
209-218,
2001[ISI][Medline].
180.
Wald, H,
Garty H,
Palmer LG,
and
Popovtzer MM.
Differential regulation of ROMK expression in kidney cortex and medulla by aldosterone and potassium.
Am J Physiol Renal Physiol
275:
F239-F245,
1998
181.
Wald, H,
Goldstein O,
Asher C,
Yagil Y,
and
Garty H.
Aldosterone induction and epithelial distribution of CHIF.
Am J Physiol Renal Fluid Electrolyte Physiol
271:
F322-F329,
1996
182.
Wald, H,
Popovtzer MM,
and
Garty H.
Differential regulation of CHIF mRNA by potassium intake and aldosterone.
Am J Physiol Renal Physiol
272:
F617-F623,
1997
183.
Waltner-Law, M,
Daniels MC,
Sutherland C,
and
Granner DK.
NF-kappa B inhibits glucocorticoid and cAMP-mediated expression of the phosphoenolpyruvate carboxykinase gene.
J Biol Chem
275:
31847-31856,
2000
184.
Wang, HC,
Zentner MD,
Deng HT,
Kim KJ,
Wu R,
Yang PC,
and
Ann DK.
Oxidative stress disrupts glucocorticoid hormone-dependent transcription of the amiloride-sensitive epithelial sodium channel alpha-subunit in lung epithelial cells through ERK-dependent and thioredoxin-sensitive pathways.
J Biol Chem
275:
8600-8609,
2000
185.
Wang, J,
Barbry P,
Maiyar AC,
Rozansky DJ,
Bhargava A,
Leong M,
Firestone GL,
and
Pearce D.
SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
Am J Physiol Renal Physiol
280:
F303-F313,
2001
186.
Webster, MK,
Goya L,
and
Firestone GL.
Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase.
J Biol Chem
268:
11482-11485,
1993
187.
Webster, MK,
Goya L,
Ge Y,
Maiyar AC,
and
Firestone GL.
Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum.
Mol Cell Biol
13:
2031-2040,
1993[Abstract].
188.
Wehling, M.
Specific, nongenomic actions of steroid hormones.
Annu Rev Physiol
59:
365-393,
1997[ISI][Medline].
189.
Weisz, OA,
Wang JM,
Edinger RS,
and
Johnson JP.
Non-coordinate regulation of endogenous epithelial sodium channel (ENaC) subunit expression at the apical membrane of A6 cells in response to various transporting conditions.
J Biol Chem
275:
39886-39893,
2000
190.
Woo, PL,
Ching D,
Guan Y,
and
Firestone GL.
Requirement for Ras and phosphatidylinositol 3-kinase signaling uncouples the glucocorticoid-induced junctional organization and transepithelial electrical resistance in mammary tumor cells.
J Biol Chem
274:
32818-32828,
1999
191.
Wulff, P,
Vallon V,
Huang DY,
Pfaff I,
Klingel K,
Kauselmann D,
Volkl H,
Lang F,
and
Kuhl D.
Deficient salt retention in the SGK1 knockout mouse (Abstract).
J Am Soc Nephrol
12:
44A,
2001.
192.
Yan, J,
Roy S,
Apolloni A,
Lane A,
and
Hancock JF.
Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase.
J Biol Chem
273:
24052-24056,
1998
193.
Yang-Yen, HF,
Chambard JC,
Sun YL,
Smeal T,
Schmidt TJ,
Drouin J,
and
Karin M.
Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein- protein interaction.
Cell
62:
1205-1215,
1990[ISI][Medline].
194.
Zecevic M, Summa V, Bens M, Vandewalle A, Pearce D, and Verrey F. Does SGK mediate aldosterone action on both apical (ENaC) and
basolateral (Na,K ATPase) Na transport proteins (Abstract)?
J Am Soc Nephrol 12: 45A. 2001.
195.
Zennaro, MC,
Farman N,
Bonvalet JP,
and
Lombes M.
Tissue-specific expression of alpha and beta messenger ribonucleic acid isoforms of the human mineralocorticoid receptor in normal and pathological states.
J Clin Endocrinol Metab
82:
1345-1352,
1997
196.
Zennaro, MC,
Souque A,
Viengchareun S,
Poisson E,
and
Lombes M.
A new human mr splice variant is a ligand-independent transactivator modulating corticosteroid action.
Mol Endocrinol
15:
1586-1598,
2001
197.
Zentner, MD,
Lin HH,
Deng HT,
Kim KJ,
Shih HM,
and
Ann DK.
Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells.
J Biol Chem
276:
29805-29814,
2001
198.
Zentner, MD,
Lin HH,
Wen X,
Kim KJ,
and
Ann DK.
The amiloride-sensitive epithelial sodium channel alpha-subunit is transcriptionally down-regulated in rat parotid cells by the extracellular signal-regulated protein kinase pathway.
J Biol Chem
273:
30770-30776,
1998
199.
Zhang, BH,
Tang ED,
Zhu T,
Greenberg ME,
Vojtek AB,
and
Guan KL.
Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf.
J Biol Chem
276:
31620-31626,
2001
200.
Zhang, Z,
Jones S,
Hagood JS,
Fuentes NL,
and
Fuller GM.
STAT3 acts as a co-activator of glucocorticoid receptor signaling.
J Biol Chem
272:
30607-30610,
1997
201.
Zhou, MY,
Gomez-Sanchez CE,
and
Gomez-Sanchez EP.
An alternatively spliced rat mineralocorticoid receptor mRNA causing truncation of the steroid binding domain.
Mol Cell Endocrinol
159:
125-131,
2000[ISI][Medline].
202.
Zimmermann, S,
and
Moelling K.
Phosphorylation and regulation of Raf by Akt (protein kinase B).
Science
286:
1741-1744,
1999