Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

Chen, Songcang; McCormick, James A.; Prabaker, Kavitha; Wang, Jian; Pearce, David; Gardner, David G.

doi:10.1161/01.hyp.0000121883.55722.45

Cited by 21 publications

(20 citation statements)

References 21 publications

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“…We have shown previously that increased extracellular tonicity leads to an increase in NPR-A gene expression and NPR-A activity (41), with concomitant increased expression of Sgk1 (40). We have hypothesized that it is Sgk1 that mediates the increase in NPR-A expression, a hypothesis that draws strength from the siRNA stud- OSM, osmolality.…”

Section: Sgk1 Is a Physiological Target Of Extracellular Tonicity In mentioning

confidence: 97%

“…The mechanism and the underlying physiological function of hypertonicity-induced SGK1 gene expression remain unclear. We have shown previously that Sgk1, which is avidly expressed in the renal medulla (39), is stimulated by increased extracellular tonicity in inner medullary collecting duct (IMCD) cells of the kidney (40). We have also demonstrated that hypertonicity increases expression of the type A natriuretic peptide receptor (NPR-A) (41), a guanylyl cyclase-linked receptor that binds both atrial natriuretic peptide (ANP) and the B-type natriuretic peptide (BNP), leading to an increase in renal excretion of sodium.…”

Section: Introductionmentioning

confidence: 99%

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Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Chen¹,

Grigsby²,

Law³

et al. 2009

J. Clin. Invest.

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202

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In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum-and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1 -/-mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. IntroductionPersistent hypertonicity, typically reflecting a high extracellular sodium concentration, stresses mammalian cells due to the ensuing osmotic efflux of water that shrinks the cells and concentrates their contents. Under most conditions, the concentration of extracellular sodium in mammals is controlled primarily through regulation of water metabolism. As extracellular sodium and plasma tonicity rise, the thirst mechanism is activated, and secretion of the neurohypophyseal hormone vasopressin into plasma increases. Vasopressin binds to its cognate receptors in the collecting duct of the kidney, resulting in increased water retention.Following short-term water restriction, several mammals demonstrate an acute increase in urinary sodium excretion that is independent of changes in water metabolism. This response, termed dehydration natriuresis (1-11), plays an important role in preventing further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. A similar natriuresis is seen following infusion of hypertonic saline (12). Investigations to date have suggested a role for central versus peripheral osmoreceptors and blood-borne versus neural effectors in contributing to dehydration-induced natriuresis; however, the precise mechanism(s) underlying this natriuresis remains undefined.

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Section: Sgk1 Is a Physiological Target Of Extracellular Tonicity In mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Chen¹,

Grigsby²,

Law³

et al. 2009

J. Clin. Invest.

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202

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“…Serum and glucocorticoid inducible kinase (Sgk) is thought to be involved in sodium handling in distal tubular segments. Chen et al 21 report exposure of IMCD cells to increasing concentrations of sodium produces an increase in Sgk levels. IMCD transfected with a Sgk vector together with a GC-A luciferase reporter exhibited a 3-fold increment in reporter gene activity.…”

Section: Gc-a Receptormentioning

confidence: 99%

Natriuretic Peptides

Richards

2007

Hypertension

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In the 25 years since de Bold et al demonstrated the existence of an atrial natriuretic factor, investigation of the cardiac natriuretic peptides has produced a maturing knowledge base 1,2 identifying the cardiac peptides and addressing stimuli for secretion of atrial (ANP) and B-type (BNP) natriuretic peptides, the processing and release of the mature bioactive carboxy terminal peptides, together with their propeptides and amino terminal fragments, the nature of natriuretic peptide receptors, and the bioactivities of natriuretic peptides (including natriuresis, vasodilatation, suppression of renin-angiotensin-aldosterone and sympathetic nervous activity, and trophic effects inhibiting vascular and cardiac hypertrophy and fibrosis). Less is known of the more recently discovered C-type natriuretic peptide (CNP and its cosecreted amino-terminal peptide, NTproCNP). 3,4 Increasingly, measurements of the B-type peptides have found diagnostic and prognostic application in cardiovascular disease. [5][6][7] The genes for ANP and BNP are in tandem on human chromosome 1. 8 Upstream regulatory regions identified for the BNP gene include an AP1 binding site, serum response elements, M-CAT and GATA sites. 9,10 Translation results in pre-pro BNP from which a 26 amino acid signal peptide is cleaved to produce the 108 amino acid precursor proBNP. This in turn is processed between amino acid residues 76 and 77 resulting in a 32 amino acid biologically active peptide (BNP) from its carboxy terminal plus the remaining amino terminal peptide sequence (NTproBNP 1 to 76). ANP is synthesized as a 126 amino acid precursor and is stored in granules within atrial tissue. 11 During or shortly after secretion, the precursor is processed to an active 28 amino acid carboxy terminal peptide (ANP) and amino terminal ANP (proANP 1 to 98). The amino terminal propeptides NTproANP, NTproBNP, and NTproCNP have no known biological actions. The mature bioactive human forms of ANP, BNP, and CNP all contain a 17 member amino acid ring bound by cysteine-to-cysteine disulphide bonds with 11 of the 16 residues being conserved across ANP, BNP, and CNP. The 3 peptides have varying length amino terminal and carboxy terminal amino acid residue "tails" with CNP essentially lacking any carboxy terminal extension beyond the ring structure. The actions of ANP and BNP are mediated predominantly via the GC-A receptor and those of CNP via the GC-B receptor. All 3 peptides are subject to varying degrees of degradation by neutral endopeptidase (EC 3.4.24.11) and via uptake by the C ("clearance") receptor.ANP and BNP and their receptors are widely distributed in brain, spinal cord, pituitary, kidney, adrenal gland, and vasculature in addition to the heart. Concentrations of immunoreactive ANP and BNP within the heart are up to 3 orders of magnitude higher than elsewhere, and within cardiac atria the concentrations of both peptides are 1 to 2 orders of magnitude higher than in ventricle. 12 CNP is also widely distributed mainly in the vasculature with far lower cardiac ...

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“…This dissociation between Sgk1 mRNA and protein expression may indicate some regulation on the translational level. Sgk1 is a cell volumeregulated gene transcriptionally upregulated by cell shrinkage (67), and a more recent study showed Sgk1-mediated osmotic induction of type A natriuretic peptide receptor (NPR-A) gene promoter in cultured cells from rat inner medullary collecting duct (14). Thus Sgk1 may contribute to cell volume regulation in the inner medulla during osmotic challenges, although its protein expression is low under basal conditions.…”

Section: Expression Under Basal Conditionsmentioning

confidence: 99%

Role of Sgk1 in salt and potassium homeostasis

Vallon¹,

Wulff²,

Huang³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Aldosterone plays a pivotal role in NaCl and K+ homeostasis by stimulation of Na+ reabsorption and K+ secretion in the aldosterone-sensitive distal nephron (ASDN). Recent studies demonstrated that the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by aldosterone in the ASDN and that polymorphisms of the kinase associate with arterial blood pressure in normotensive subjects. This review discusses the role of Sgk1 in NaCl and K+ homeostasis as evidenced by in vivo studies, including those in Sgk1-deficient mice. The studies indicate that Sgk1 is not absolutely required for Na+ reabsorption and K+ secretion in the ASDN. On a standard NaCl and K+ diet, modestly enhanced plasma aldosterone concentrations appear sufficient to establish a compensated phenotype in the absence of Sgk1. The kinase is necessary, however, for upregulation of transcellular Na+ reabsorption in the ASDN. This may involve Sgk1-mediated stimulation of basolateral Na+-K+-ATPase as well as retention of epithelial Na+ channel, ENaC, in the apical membrane. Such an upregulation is a prerequisite for adequate adaptation of 1) renal NaCl reabsorption during restricted dietary NaCl intake, as well as 2) K+ secretion in response to enhanced K+ intake. Thus gain-of-function mutations of Sgk1 are expected to result in renal NaCl retention and enhanced K+ secretion. Further studies are required to elucidate renal and nonrenal aldosterone-induced effects of Sgk1, the role of other Sgk1 activators, as well as the link of Sgk1 polymorphisms to arterial hypertension in humans.

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Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

Cited by 21 publications

References 21 publications

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Natriuretic Peptides

Role of Sgk1 in salt and potassium homeostasis

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