Phosphoinositide 3-kinase is required for  aldosterone-regulated sodium reabsorption

Blazer‐Yost, Bonnie L.; Păunescu, Teodor G.; Helman, S. I.; Lee, Kimberly D.; Vlahos, Chris J.

doi:10.1152/ajpcell.1999.277.3.c531

Cited by 120 publications

(126 citation statements)

References 21 publications

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“…The effects of aldosterone and insulin or IGF-1 may be additive [17]. Insulin stimulates SGK1 and is thus expected to enhance ENaC activity and renal Na + reabsorption [6][7][8]. SGK1 contributes to the regulation of renal Na + excretion by aldosterone, insulin, and IGF-1.…”

Section: Discussionmentioning

confidence: 99%

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Artunc

Sandulache

Nasir

et al. 2008

Pflugers Arch - Eur J Physiol

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PPARγ-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARγ-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARγ agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na + channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARγ agonists. To test this hypothesis, food containing the PPARγ agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1 −/− , n=12) and their wild-type littermates (sgk1 +/+ , n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1 +/+ mice. The treatment increased body weight significantly in both, sgk1 +/+ mice (+2.2±0.3 g) and sgk −/− mice (+1.3±0.2 g), and decreased hematocrit significantly in sgk1 +/+ mice (−6.5±1.0%) and sgk1 −/− mice (−3.1±0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1 +/+ mice. According to Evans Blue

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Section: Discussionmentioning

confidence: 99%

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Artunc

Sandulache

Nasir

et al. 2008

Pflugers Arch - Eur J Physiol

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“…22,23 ENaC upregulation by mineralocorticoids requires activation through the PI3 kinase pathway, which mediates the stimulation of renal Na ϩ excretion by insulin and IGF1. 24 Thus, SGK1 may participate in the signaling of IGF1-induced alterations of renal Na ϩ transport and blood pressure. Acromegaly, which leads to enhanced release of IGF1, is a well-known cause of hypertension, and the IGF1 gene locus demonstrates linkage to blood pressure in twins.…”

Section: Discussionmentioning

confidence: 99%

Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure

et al. 2002

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Abstract-The serum-and glucose-regulated kinase (SGK1) gene has recently been identified as an important aldosterone-induced protein kinase that mediates trafficking of the renal epithelial Na ϩ channel (ENaC) to the cell membrane. Thus, SGK1 is an appealing candidate for blood pressure regulation and possibly essential hypertension. To test this hypothesis, we recruited monozygotic (126 pairs) and dizygotic (70 pairs) normotensive twin subjects and parents of dizygotic twins. Blood pressure was measured in a controlled fashion: recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S1038, and D6S270) and 2 single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (PϽ0.0002) and suggestive evidence for linkage for systolic blood pressure (PϽ0.04), documenting the locus as a quantitative trait locus for blood pressure. We next performed association, using all dizygotic twins and a monozygotic member from each pair. We found significant associations between both single nucleotide polymorphism variants and blood pressure, as well as a significant interaction between the single nucleotide polymorphisms enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. We conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.

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“…However, its role has not attracted as much attention because, under normal conditions, basal PIP 3 levels are very low in cells, even though it is well known that PIP 3 can be generated from PIP 2 by activation of phosphotidylinositol-3-kinase (PI 3-K). Recent studies suggest that both aldosterone and insulin enhance Na ϩ transport by activating PI 3-K in A6 cells (26 -28) and that the concentration of PIP 3 in A6 cells is elevated in response to aldosterone (26). Recent studies have also shown that not only PIP 2 but also other anionic phospholipids, including PIP 3 , acutely regulate ENaC activity in A6 cells (18,29).…”

Section: Stimulation Of Steroid Receptors Increases Membrane Pip 3 Anmentioning

confidence: 99%

Acute Regulation of Epithelial Sodium Channel by Anionic Phospholipids

Eaton

2005

Journal of the American Society of Nephrology

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Anionic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) are normally located in the inner leaflet of the plasma membrane, where these anionic phospholipids can regulate transmembrane proteins, including ion channels and transporters. Recent work has demonstrated that (1) ATP inhibits the renal epithelial sodium channel (ENaC) via a phospholipase C-dependent pathway that reduces PIP 2 , (2) aldosterone stimulates ENaC via phosphoinositide 3-kinase, and (3) PIP 2 and PIP 3 regulate ENaC. Several lines of evidence show that ATP stimulation of purinergic P2Y receptors hydrolyzes PIP 2 and that aldosterone stimulation of steroid receptors induces PIP 3 formation. These studies together suggest that one primary mechanism for regulating ENaC is by alteration of anionic phospholipids and that the receptor-mediated and hormonal regulation of ENaC works through a variety of signaling pathways, but many of these pathways finally alter ENaC activity by regulating the formation or degradation of anionic phospholipids. Therefore, changes in the concentration of PIP 2 and PIP 3 are hypothesized to participate in the regulation of ENaC by purinergic and corticoid receptors. The underlying mechanism may be associated with a physical interaction of the positively charged cytoplasmic domains of the ␤-and ␥-ENaC with the negatively charged membrane phospholipids. The exact nature of this interaction will require further investigation. T he phospholipid compositions of the two leaflets of the lipid bilayer that forms the plasma membrane are strikingly different. Anionic phospholipids are normally located in the inner leaflet to form a negatively charged surface. However, whether the phospholipid asymmetry affects the function of transmembrane proteins remains largely unknown. Recent studies have shown that one of the anionic phospholipids, phosphatidylinositol 4,5-bisphosphate (PIP 2 ), regulates Na ϩ -Ca 2ϩ exchangers and inward rectifier potassium channels (1-4). Besides PIP 2 , phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), regulates ATP-sensitive potassium (K ATP ) channels (5,6). A model for the regulation of K ATP channels by anionic phospholipids has been proposed; the negatively charged head group of PIP 2 or PIP 3 locks the positively charged carboxyl terminus of K ATP channels in an open conformation and prevents ATP binding to the cytosolic terminus (7). These recent studies suggest that anionic phospholipids may interact with the positively charged cytoplasmic termini of other ion channels and transporters. In this review, we focus primarily on the mechanism by which changes in cellular anionic phospholipids such as PIP 2 and PIP 3 regulate the renal epithelial sodium channel (ENaC) and then speculate on a possible underlying mechanism. Stimulation of Purinergic P2Y Receptors Decreases Membrane PIP 2 and ENaC ActivityIt is known that ATP binds to the purinergic P2Y receptor family, G protein-coupled receptors that activate phospholipase C (PLC...

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Phosphoinositide 3-kinase is required for aldosterone-regulated sodium reabsorption

Cited by 120 publications

References 21 publications

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure

Acute Regulation of Epithelial Sodium Channel by Anionic Phospholipids

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