SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport

Wang, Jian; Barbry, Pascal; Maiyar, Anita C.; Rozansky, David J.; Bhargava, Aditi; Leong, Meredith L.; Firestone, Gary L.; Pearce, David

doi:10.1152/ajprenal.2001.280.2.f303

Cited by 190 publications

(236 citation statements)

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“…Furthermore, there is evidence that aldosterone can affect insulin receptor mRNA levels, at least in cultured cells (36), and aldosterone levels have been correlated with insulin resistance (37). Finally, aldosterone induces the expression of the serum glucocorticoid-inducible kinase gene, whose expression level also responds to changes in glucose and insulin levels (38,39), suggesting yet another potential connection between aldosterone and glucose homeostasis. Alternatively, it is possible that arginine at residue 173 affects the activity of aldosterone synthase such that the rate of conversion of an intermediate to aldosterone is reduced.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in aldosterone synthase predicts plasma glucose levels

Ranade

Risch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms-one in the putative promoter (T-344C) and another resulting in a lysine͞arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population-were associated with fasting plasma glucose levels (P ‫؍‬ 0.000017) and those 60 (P ‫؍‬ 0.017) and 120 (P ‫؍‬ 0.0019) min after an oral glucose challenge. A C͞T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39 -3.92; P ‫؍‬ 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P ‫؍‬ 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.H ypertension affects 15-50% of the adult population and is one of the major risk factors for stroke, myocardial infarction, and renal disease. Despite intense effort, our understanding of heritable factors in the etiology of hypertension is rather poor. Twin, adoption, and epidemiologic studies indicate that variation in blood pressure (BP) is genetically determined to some extent (1-3). Insulin resistance, defined as the sluggish uptake of glucose by peripheral tissue in the presence of normal or elevated levels of insulin, is frequently associated with hypertension (4). One of the goals of the Stanford, Asia, and Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) study is to identify predisposing genes for essential hypertension and insulin resistance.To maximize our chances of finding susceptibility genes for these diseases, we took several steps. First, in an attempt to reduce genetic heterogeneity, we focused on a relatively homogeneous population of Chinese and Japanese descent. Second, we sampled subjects from tails of the systolic or diastolic BP distributions-the affected hypertensives were recruited from the upper 20% of the distribution, whereas the unaffected ''low-normotensive'' individuals had BP readings in the lower 30% of the distribution (5). Third, because recent theoretical work suggests that association studies might be adequately powerful to detect susceptibility loci that have a modest effect on the phenotype (6), we began candidate gene studies by testing specific variants in genes that might, for biological reasons, be expected to be involved in BP regulation or glucose homeostasis for association with hypertension or insulin resistance.The mineralocorticoid hormone, aldosterone, by determining the amount of sodium and water reabsorbed by the kidney, plays a key role in regulating BP (7). Indeed, mutations in the aldosterone synthase gene or in the receptor for the hormone can cause Mendelian forms of hypertension and hypotension ...

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Section: Discussionmentioning

confidence: 99%

Genetic variation in aldosterone synthase predicts plasma glucose levels

Ranade

Risch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…In this context it is interesting to note that SGK1 has been reported to physically interact with the Cterminal tails of ␣-ENaC and ␤-ENaC in vitro. However, there was no evidence that this association resulted in ENaC phosphorylation (25). Thus, as far as we know, specific phosphorylation of the serine residue 621 within the SGK consensus motif of ␣-ENaC has not yet been reported.…”

Section: Fig 10mentioning

confidence: 95%

“…This was initially demonstrated by co-expression experiments in Xenopus laevis oocyte (16,18,21,22) and more recently in cultured renal epithelial cells (23,24). SGK1 is thought to be an important molecular target that integrates multiple endocrine inputs regulating epithelial sodium transport (24,25). The recent development of SGK1 null mice has confirmed that the presence of SGK1 is important for the maintenance of sodium balance, since these animals develop pseudohypoaldosteronism when kept on a low sodium diet (26).…”

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confidence: 99%

A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit

Diakov

Korbmacher

2004

Journal of Biological Chemistry

156

145

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Aldosterone-induced serum-and glucocorticoid-inducible kinase isoform 1 (SGK1) contributes to the regulation of the epithelial sodium channel (ENaC), the activity of which is critical for long term blood pressure control. Aldosterone-induced SGK1 is thought to enhance ENaC surface expression by phosphorylating Nedd4-2 and thereby preventing ENaC retrieval and degradation. In outside-out membrane patches of Xenopus laevis oocytes heterologously expressing ENaC, amiloride-sensitive ENaC currents were enhanced by phosphatase inhibitors and were dependent on cytosolic Mg 2؉ . This indicates that a kinase is involved in channel regulation. Indeed, recombinant constitutively active SGK1, included in the pipette solution, caused a sustained 2-to 3-fold increase of ENaC currents. Deletion of the C terminus of ␣ENaC largely reduced the stimulatory effect of SGK1, whereas stimulation by SGK1 did not require the presence of the C termini of the ␤-or ␥-subunits. Replacing the serine residue Ser 621 of the SGK1 consensus motif in the C terminus of the ␣-subunit by an alanine specifically abolished the stimulatory effect of SGK. Our findings indicate that SGK1 can stimulate ENaC activity independently of an inhibition of Nedd4-2-mediated channel retrieval. This defines a novel regulatory pathway likely to be relevant for aldosterone-induced stimulation of ENaC in vivo.The appropriate regulation of the epithelial sodium channel (ENaC) 1 in the kidney is critically important for the maintenance of body sodium balance and hence for long term regulation of arterial blood pressure (1). Indeed, two human genetic diseases provide direct evidence that molecular dysfunction of ENaC has severe effects on arterial blood pressure. Loss-offunction mutations of ENaC cause urinary sodium loss, hyperkalemia, and low blood pressure in patients with pseudohypoaldosteronism type 1 (2). In contrast, gain-of-function mutations of ENaC are found in patients with so-called Liddle's syndrome (pseudohyperaldosteronism) and result in increased renal sodium re-absorption, hypokalemia, and severe arterial hypertension (3).ENaC is composed of three subunits called ␣, ␤, and ␥ (4). The C termini of the ENaC subunits each contain a proline-rich PPXY (PY) motif, which is believed to be important for interaction with the ubiquitin-protein ligases Nedd4 and Nedd4-2, promoting the ubiquitination, endocytosis, and proteasomal degradation of the channel (5-8). The functional importance of the PY motif was recognized in Liddle's syndrome where mutations and/or deletions of the PY motif in ␤ or ␥ ENaC reduce the endocytic retrieval of ENaC from the membrane (9, 10). This results in an increase in the number of ENaC channels in the membrane, which in turn is thought to cause hyperabsorption of Na ϩ and hypertension in patients with Liddle's syndrome (11,12).The most important hormone to regulate ENaC activity is the mineralocorticoid aldosterone. The effects of aldosterone include transcriptional, translational, and post-translational modifications of ENaC and inv...

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“…Aldosterone-and insulin-mediated regulation of ENaC occurs through SGK1-mediated inhibition of Nedd4-2. 31, 101 Since these initial discoveries, a complex array of kinases has been shown to regulate ENaC directly and indirectly. For the purposes of this review, only recent discoveries are discussed.…”

Section: Intrinsic Factorsmentioning

confidence: 99%