Targeting SGK1 in diabetes

doi:10.1517/14728220903260807

Expert Opin Ther Targets. Author manuscript; available in PMC 2010 November 1.

Published in final edited form as:

Expert Opin Ther Targets. 2009 November; 13(11): 1303–1311.

doi: 10.1517/14728220903260807

PMCID: PMC2798808

NIHMSID: NIHMS160413

Targeting SGK1 in diabetes

Florian Lang, Agnes Görlach, and Volker Vallon

Eberhard-Karls-University of Tuebingen, Department of Physiology, Gmelinstrasse 5, Tuebingen 72076, Germany

Corresponding author.

The publisher's final edited version of this article is available at Expert Opin Ther Targets

See other articles in PMC that cite the published article.

Abstract

Compelling evidence is accumulating pointing to a pathophysiological role of the serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in the development and complications of diabetes. SGK1 is ubiquitously expressed with exquisitely high transcriptional volatility. Stimulators of SGK1 expression include hyperglycemia, cell shrinkage, ischemia, glucocorticoids and mineralocorticoids. SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase, 3-phosphoinositide dependent kinase PDK1 and mTOR. SGK1 activates ion channels (including ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and CLCKa/Barttin), carriers (including NCC, NKCC, NHE3, SGLT1 and EAAT3), and the Na⁺/K⁺-ATPase. It regulates the activity of several enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead-transcription-factor FOXO3a, β-catenin, nuclear-factor-kappa-B NFκB). A common SGK1 gene variant (~3–5% prevalence in Caucasians, ~10% in Africans) is associated with increased blood pressure, obesity and type 2 diabetes. In patients suffering from type 2 diabetes, SGK1 presumably contributes to fluid retention and hypertension, enhanced coagulation, and increased deposition of matrix proteins leading to tissue fibrosis such as diabetic nephropathy. Accordingly, targeting SGK1 may favourably influence occurrence and course of type 2 diabetes.

Keywords: Coagulation, Fibrosis, Hypertension, Inflammation, Metabolic syndrome

1. Introduction

The serum- and glucocorticoid-inducible kinase 1 (SGK1) was discovered as a gene regulated transcriptionally by serum- and glucocorticoids in rat mammary tumor cells [1]. The human isoform was cloned as an immediate early gene upregulated by cell shrinkage [2].

SGK1 transcripts are found in virtually all tissues, but their level varies between different cell types in brain [3], eye [4], inner ear [5–7], semicircular canal duct epithelium [6], lung [3, 8, 9], kidney [10], liver, intestine, pancreas and ovary [4]. Expression patterns depend on the developmental state [4, 11].

In humans, the SGK1 encoding gene is localised in chromosome 6q23 [4]. Several translational SGK1 variants have been identified, which differ in regulation of expression, subcellular localization and function [12–14]. SGK1 forms dimers by two intermolecular disulfide bonds between Cys258 in the activation loop and Cys193 [15].

SGK1 stimulates a variety of ion channels, transporters, transcription factors and enzymes [4]. The kinase thus participates in the regulation of a wide variety of functions (for earlier reviews see [4, 16]). In the present review, the case is made that SGK1 plays a dual role in the pathophysiology of diabetes. At the one hand, it facilitates the development of obesity, which in turn predisposes to the development of type 2 diabetes. On the other hand, it is upregulated by hyperglycemia and contributes to the development of hypertension, excessive coagulation and fibrosis in the affected patients.

2. Transcriptional SGK1 regulation

As evidenced from Northern blotting, RT-PCR and/or in situ hybridisation, SGK1 transcription is stimulated by glucocorticoids [1, 17], mineralocorticoids [18, 19], gonadotropins [4]., progestin [20], progesterone, 1,25-dyhydroxyvitamin D₃ (1,25(OH)₂D₃), transforming growth factor β (TGFβ), interleukin 6, fibroblast and platelet-derived growth factor [4], thrombin [21], endothelin [4, 22], advanced glycation end products (AGE), further cytokines and activation of peroxisome proliferator-activated receptor γ [4, 23].

Additional stimulators include cell shrinkage [4], excessive glucose concentrations [4], A6 cell swelling [24], chelation of Ca²⁺ [24], metabolic acidosis [25], salt loading of spontaneously hypertensive mice [26], oxidative stress [17, 27], heat shock, UV radiation, DNA damage,ischemia, neuronal injury, neuronal excitotoxicity, neuronal challenge by exposure to microgravity, fear conditioning, plus maze exposure, enrichment training, amphetamine, lysergic acid dimethylamide LSD, electroconvulsive therapy, sleep deprivation and fluoxetine [4, 28].

Moreover, enhanced SGK1 transcript levels were observed in diabetic nephropathy [29], Rett syndrome, organ rejection, dialysis, wound healing, glomerulonephritis, liver cirrhosis, fibrosing pancreatitis, Crohn's disease, lung fibrosis and cardiac fibrosis [4, 30].

SGK1 transcription is downregulated by heparin, mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), dietary iron and nucleosides [4, 31].

Signalling molecules participating in the regulation of SGK1 transcription include cyclic AMP [20], reactive oxygen species and NADPH oxidases [21], protein kinase C, protein kinase Raf, big mitogen-activated protein kinase 1 (BMK1), mitogen-activated protein kinase (MKK1), stress-activated protein kinase-2 (SAPK2, p38 kinase), phosphatidylinositol-(PI)-3-kinase, extracellular signal-regulated kinase (ERK1/2), p53, cytosolic Ca²⁺, nitric oxide, EWS/NOR1(NR4A3) fusion protein [4, 32],

The promoter of the rat SGK1 gene contains binding sites for several transcription factors including receptors for glucocorticoids (GR), mineralocorticoids (MR), progesterone (PR), the vitamin D receptor (VDR), retinoids (RXR), farnesoids (FXR), as well as sterol regulatory element binding protein (SREBP), peroxysome proliferator activator receptor gamma (PPARγ), cAMP response element binding protein (CREB), p53 tumor suppressor protein, Sp1 transcription factor, activating protein 1 (AP1), activating transcription factor 6 (ATF6), heat shock factor (HSF), reticuloendotheliosis viral oncogene homolog (c-Rel), nuclear factor κB (NFκB), signal transducers and activators of transcription (STAT), TGFβ dependent transcription factors SMAD3 and SMAD4, and fork-head activin signal transducer (FAST) [1].

3. Posttranscriptional localization and regulation of SGK1

According to immunohistochemistry, serum may trigger importin-alpha mediated entry of SGK1 into the nucleus [4] and hyperosmotic shock or glucocorticoids may increase the cytosolic SGK1 abundance [1, 4]. SGK1 has further been localized to the mitochondrial membrane [33, 34].

Activation of SGK1 is accomplished by phosphorylation at the threonine 256 by the 3-phosphoinositide (PIP3)-dependent kinase PDK1 [35]. The effect of PDK1 requires prior phosphorylation at serine 422 [35]. Further kinases involved in the activation of SGK1 include the mammalian target of rapamycin mTOR and the serine/threonine kinase WNK1 (with no lysine kinase 1) [4, 36–40]. PIP3 is degraded and thus PDK1 dependent SGK1 activation is disrupted by the phosphatase and tensin homolog PTEN [4]. The assembly of SGK1 and PDK1 and the subsequent SGK1 activation is supported by the scaffold protein Na⁺/H⁺ exchanger regulating factor 2 (NHERF2) [4].

PDK1 dependent activation of SGK1 is triggered via PI3-kinase by insulin, IGF1, hepatic growth factor (HGF), follicle stimulating hormone (FSH) and thrombin [4]. SGK1 is further activated by bone marrow kinase/extracellular signal-regulated kinase 5 (BK/ERK5), p38α, feeding, increased cytosolic Ca²⁺ activity with subsequent activation of calmodulin-dependent protein kinase kinase (CaMKK), the G-protein Rac1, neuronal depolarization, cAMP, lithium, oxidation and adhesion to fibronectin [4, 21, 41].

SGK1 is ubiquitinated by the ubiquitin ligase Nedd4-2 (neuronal precursor cells expressed developmentally downregulated) and is rapidly degraded leading to a half-life of some 30 minutes [4].

4. SGK1 regulated proteins

SGK1 may phosphorylate proteins at the consensus sequence R-X-R-X-X-(S/T)-phi (X = any amino acid, R = arginine, phi = hydrophobic amino acid), which is similar to that of related kinases [4]. The only proteins hitherto known to be exclusive SGK1 targets are N-myc downregulated genes NDRG1 and NDRG2. Acccordingly, most SGK1 sensitive functions are similarly regulated by the SGK and protein kinase B isoforms or other related kinases. A specific inhibitor against SGK1 would thus not be expected to abrogate those functions [4].

SGK1 stimulates a wide variety of channels including the epithelial Na⁺ channel ENaC [4, 42–51], the voltage gated Na+ channel SCN5A [4], the renal outer medullary K⁺ channel ROMK1 [4], the voltage gated K⁺ channels KCNE1/KCNQ1 [52]. KCNQ4 [4], Kv1.3, Kv1.5 [53] and Kv4.3 (K⁺ channel) [4], the epithelial Ca²⁺ channels TRPV5 [4] and TRPV6 [54], the kainate receptor GluR6 [4], the unselective cation channel 4F2/LAT [4], the Cl⁻ channels ClCka/barttin [55], ClC2 [4], CFTR (Cystic fibrosis transmembrane conductance regulator) [56, 57] and VSOAC (volume-sensitive osmolyte and anion channel) [4], as well as the acid sensing ion channel ASIC1 [58].

SGK1 stimulates a number of carriers including the the NaCl cotransporter NCC [59], the Na⁺,K⁺,2Cl⁻ cotransporter NKCC2 [4], the Na⁺/H⁺ exchanger NHE3 [60, 61], the glucose transporters SGLT1 [62–64], GLUT1 [65] and GLUT4 [66], the amino acid transporters ASCT2 [66], SN1 [4], EAAT1 [4], EAAT2 [4], EAAT3 [4], EAAT4 [67] and EAAT5 [4], the peptide transporter PepT2 [68], the Na⁺,dicarboxylate cotransporter NaDC-1 [4], the creatine transporter CreaT [4], the Na⁺, myoinositol cotransporter SMIT [69], as well as the phosphate carrier NaPiIIb [4]. SGK1 further stimulates the Na⁺/K⁺-ATPase [4, 70].

SGK1 may regulate channels, carriers and the Na⁺/K⁺-ATPase by modification of expression [71], by phosphorylating the target proteins or by phosphorylating the ubiquitin ligase Nedd4-2 [16]. Following SGK1-dependent phosphorylation, Nedd4-2 binds to a heterodimeric protein complex composed of 14-3-3beta and 14-3-3epsilon [72] and is thus unable to ubiquitinate its targets [73, 74]. The result is reduced degradation of the target proteins, such as ENaC. Both 14-3-3 isoforms are upregulated by aldosterone [72]. Silencing of the proteins abrogates the stimulating effect of aldosterone on ENaC [72].

SGK1 may further be effective by inhibiting inducible nitric oxide synthase iNOS leading to decreased formation of nitric oxide, which in turn may modify transport [75]. Moreover, SGK1 may regulate carriers and channels through activation of the phosphatidylinositol-3-phosphate-5-kinase PIKfyve and subsequent formation of PIP2 [64, 76, 77] or by inhibition of WNK4, which in turn inhibits ENaC [78].

Beyond its effect on Nedd4-2, iNOS [75], PIKfyve [64, 76, 77] and WNK4 [78], SGK1 may phosphorylate and thus inhibit several further enzymes, including the mitogen-activated protein kinase/ERK kinase kinase 3 MEKK3, the stress activated kinase SEK1 [17], the B-Raf kinase, the phosphomannose mutase 2, and the glycogen synthase kinase 3 GSK3 [4].

SGK1 regulates a number of transcription factors, including the cAMP responsive element binding protein (CREB), the nuclear factor kappa B (NFκB) [79, 80]., and the forkhead transcription factor FKHR-L1 (FOXO3a) [4, 21, 81].

SGK1 phosphorylates several additonal proteins including the type A natriuretic peptide receptor (NPR-A), Ca²⁺ regulated heat-stable protein of apparent molecular mass 24 kDa CRHSP24, the adaptor precursor (APP) Fe65, NDRG1 and NDRG2, mosinVc, filamin C, microtubule-associated protein tau and huntingtin [4, 46, 82].

It should be pointed out again, that most targets are shared by related kinases, which usually play a leading part over SGK1 in the regulation of the respective targets [4]. SGK3-regulated target proteins include ENaC, TRPV5,6, SCN5A, GluR1, the rapid delayed voltage gated cardiac K⁺ channels (HERG), several voltage gated (Kv) channels, KCNE1/KCNQ1, CLC-Ka/barttin, the carriers SGLT1, several amino acid carriers, creatine transporter SLC6A8, Na⁺ dicarboxylate cotransporter and the Na⁺/K⁺-ATPase [4, 54, 69]. SGK3 further phosphorylates glycogen synthase kinase 3 beta (GSK-3beta) [4]. Less is known about functions of SGK2, which, however, similarly regulates ENaC, Kv channels, KCNE1/KCNQ1, CLCKa/barttin, several amino acid transporters, the Na+ dicarboxylate cotransporter 1 and the Na+/K+-ATPase [4, 69, 83].

5. SGK1 sensitive functions

SGK1 dependent regulation affects a wide variety of physiological and pathophysiological functions [4] including regulation of cell volume [84], cell survival and tumor growth [85], cell proliferation, aldosterone release, insulin release [86], induction and maintenance of neuropathic and inflammatory pain [87], glucose metabolism, function of decidualizing cells [20], cellular K⁺ uptake [88], gastric acid secretion [89–91], intestinal transport, renal tubular salt- [47], K⁺- and Ca²⁺-transport as well as salt appetite [4, 92]. In Caenorhabditis elegans, knockout of SGK1 leads to substantial prolongation of life span [4]. Data addressing the putative role of SGK1 as a determinant of life span in other species have not been published. Mice lacking SGK3 have impaired hair growth [93, 94] and reduced locomotion [4].

6. Pathophysiological role of SGK1 in diabetes

Compelling evidence points to a role of SGK1 in the development of diabetes and the pathophysiology of its complications.

SGK1 participates in the development of obesity [4], which is well known to cause insulin resistance and ultimately impair insulin release leading to type 2 diabetes [95]. The mechanisms involved in the development of insulin resistance in obese individuals include intracellular lipid-induced inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation resulting in reduced IRS-1-associated phosphatidyl inositol 3 kinase activity and subsequent decrease of insulin-stimulated GLUT4 activity [96].

SGK1 fosters the development of obesity at least partially by stimulation of the Na⁺ coupled glucose transporter SGLT1, which accelerates the intestinal uptake of glucose [4]. The rapid intestinal glucose absorption leads to excessive insulin release and fat deposition, with subsequent decrease of plasma glucose concentration, which triggers repeated glucose uptake and thus obesity. Conversely, obesity could be counteracted by inhibitors of SGLT1 [4]. The role of SGK1 in the development of obesity is underscored by the observation that a variant of the SGK1 gene (the combined presence of distinct polymorphisms in intron 6 [I6CC] and in exon 8 [E8CC/CT]) is associated with increased body weight. The same SGK1 gene variant is more prevalent in patients with type 2 diabetes than in individuals without family history of diabetes [97]. The gene variant is common, affecting 3–5 % of a Caucasian population and some 10 % of an African population [97]. In diabetes mellitus, the excessive plasma glucose concentrations could, at least in theory, upregulate intestinal SGK1 expression and the enhanced SGK1-dependent stimulation of SGLT1 could contribute to the maintenance of obesity.

SGK1 is similarly important in the development of diabetic complications. As indicated above, SGK1 transcription is stimulated by excessive glucose concentrations and strong SGK1 expression has been observed in renal tissue of diabetic patients [4, 29].

Excessive SGK1 expression in diabetic nephropathy leads to stimulation of SGLT1 in proximal renal tubules which blunts the glucosuria [98]. Moreover, SGK1 could stimulate proximal renal tubular glucose transport by stimulation of the K⁺ channels KCNQ1/KCNE1, which establish the electrical driving force for electrogenic glucose transport.

The same SGK1 gene variant, which predisposes to obesity, is associated with moderately enhanced blood pressure. Individuals carrying the SGK1 gene variant display a particularly strong correlation between insulinemia and blood pressure [4], pointing to a decisive role of SGK1 in the hypertension paralleling hyperinsulinemia. In wild type mice, hyperinsulinemia by pretreatment with a high-fructose diet or a high fat diet sensitizes arterial blood pressure to high-salt intake, an effect completely lacking in SGK1-knockout mice (sgk1^−/−) [4]. Accordingly, SGK1 is required for the stimulation of renal tubular salt reabsorption by insulin. SGK1 further participates in the hypertensive effects of glucocorticoids [99]. The excessive expression of SGK1 during hyperglycemia or diabetes mellitus could, at least in theory, sensitize the renal tubules for the salt retaining effects of insulin and thus foster the development of hypertension.

Similar to excessive SGK1 activity, lack of Nedd4-2 leads to hypertension [100]. Moreover, the Nedd4-2 gene variant ^P355LNedd4-2 with enhanced SGK1 sensitivity, predisposes to the development of renal salt retention, hypertension and development of end-stage renal disease (ESRD).

SGK1-sensitive renal salt retention may not only predispose to hypertension but contribute to fluid retention and edema formation during treatment with PPARγ agonists [101] or in nephritic syndrome [102]. Along those lines, SGK1 expression is increased during ascites formation in cirrhotic rats [103].

Increased SGK1 expression and activity may further contribute to the risk of kidney stones, which are more prevalent in individuals with type II diabetes. Despite the stimulating effect of SGK1 on TRPV5 Ca²⁺ channels, the renal Ca²⁺ excretion is decreased in sgk1−/− mice [4]. Conversely, enhanced SGK1 activity is expected to foster calciuria. The stimulation of NaCl cotransport and ENaC by SGK1 leads to extracellular volume expansion, which decreases Na⁺ and Ca²⁺ reabsorption in the proximal tubule and in the thick ascending limb of the loop of Henle, thus increasing renal Ca²⁺ excretion. Conversely, inhibition of NaCl cotransport by thiazide diuretics leads to anticalciuria protecting against the development of Ca²⁺ stones, an effect involving upregulation of proximal tubular Ca²⁺ reabsorption [104].

SGK1 is expressed in glomerular podocytes [27, 105] and upregulated in those cells by aldosterone and oxidative stress [27]. SGK1 is thus thought to participate in the development of proteinuria during mineralocorticoid excess and inflammation. Accordingly, the proteinuria following DOCA treatment is significantly blunted in SGK1 knockout mice [4]. Lack of SGK1 does, however, not protect against doxorubicin induced glomerular injury [102]. Hitherto, no experiments have been published on the role of SGK1 in proteinuria of diabetic nephropathy.

SGK1 has been shown to potentiate the effect of excessive glucose concentrations on fibronectin formation [4]. Hitherto, excessive SGK1 transcription during diabetes has only been demonstrated in renal tissue and isolated cells [4]. Excessive SGK1 expression has been reported to prevail in several other tissues during fibrosing disease such as in intestinal Crohn´s disease, lung fibrosis, liver cirrhosis, and fibrosing pancreatitis [4]. Besides diabetic nephropathy, glomerulonephritis and puromycin aminonucleoside induced experimental rat nephritic syndrome are paralleled by excessive renal expression of SGK1 [4].

As indicated above, SGK1 transcription is strongly stimulated by transforming growth factor TGFβ [4], which has been identified as the etiologic agent of renal hypertrophy and the accumulation of mesangial extracellular matrix components in diabetes [106]. Accordingly, renal hypertrophy and fibrosis of diabetic mice could be reversed by neutralizing anti-TGF-beta antibodies, antisense TGF-beta1 oligodeoxynucleotides or knocking out the Smad3 gene [106].

Epidermal growth factor (EGF) has similarly been shown to play a role in the nephromegaly and enhanced sodium reabsorption observed in diabetic nephropathy [107, 108]. Experiments in primary cultures of human cortical fibroblasts revealed that high glucose concentrations stimlate the epidermal growth factor receptor EGF-R, which enhances the expression of SGK-1 with subsequent stimulation of fibronectin formation [107, 108].

SGK1 stimulates the nuclear translocation of NFκB, a transcription factor stimulating the expression of connective tissue growth factor (CTGF) [4]. CTGF is a strong stimulator of fibrosis and contributes to the stimulation of matrix protein synthesis and the development of a variety of fibrosing disorders [4]. The cardiac stimulation of CTGF formation and cardiac fibrosis following mineralocorticoid excess are completely abrogated by knockout of SGK1, an observation underscoring the causal role of SGK1 in fibrosing disease [4]. In addition, SGK1 paticipates in α-adrenergically induced cardiac hypertrophy [4].

The profibrotic effect of SGK1 may come as a surprise in view of the known anti-inflammatory effect of glucocorticoids. However, the synthetic glucocorticoid dexamethasone has previously been shown to enhance the expression of CTGF and collagen and to foster fibrosis [4].

Excessive SGK1 expression in diabetes further contributes to a prothrombotic state since SGK1 has been shown to be activated and upregulated by thrombin in a redox-dependent manner [21]. Interestingly, SGK1 can induce the expression of tissue factor, the activator of the extrinsic coagulation cascade, and promotes procoagulant activity [21].

7. Conclusions

The serum- and glucocorticoid-inducible kinase SGK1, a potent regulator of metabolism, transport, transcription and enzyme activity, plays a dual role in the pathophysiology of diabetes mellitus. At the one hand, it fosters the development of obesity, which in turn predisposes to type 2 diabetes. On the other hand it participates in the pathophysiology of diabetic complications. It is upregulated by hyperglycemia and could account for insulin induced hypertension. It presumably contributes to the enhanced incidence of nephrolithiasis, glomerular injury and the hypercoagulable state in diabetic individuals. Most importantly, it participates in the stimulation of fibrosis leading particularly to the development of diabetic nephropathy.

8. Expert Opinion

The triggering of obesity, hypertension and coagulation by SGK1 renders the kinase a signaling molecule fostering the development of metabolic syndrome, a condition associated with enhanced morbidity and mortality from cardiovascular disease [4]. Metabolic syndrome shares several clinical features with glucocorticoid excess or Cushing´s syndrome despite normal glucocorticoid plasma concentrations [4]. It is tempting to speculate that at least in some individuals, an increased glucocorticoid independent SGK1 expression accounts for metabolic syndrome. Along those lines, maternal SGK1 appears to be critically important for the fetal programming of hypertension in the offspring in response to malnutritive stress of the mother [109].

Accordingly, pharmacological SGK1 inhibition may be an attractive stratgy to counteract obesity, metabolic syndrome and the complications of diabetes mellitus. As SGK1 is apparently not required for house keeping functions [4], side effects of specific SGK1 inhibitors are expected to be modest. Accordingly, the phenotype of SGK1 knockout mice is mild [4]. SGK1 may be a particularly attractive therapeutic option in patients carrying the gain of function variant of the SGK1 gene.

Combined inhibition of SGK1 and SGK3 may still be tolerated, as the phenotype of the SGK1-SGK3 double knockout mouse is similarly mild. SGK1 inhibitors are useful, however, only, if they do not inhibit the PKB/Akt isoforms, which would impede cellular glucose uptake and thus be expected to aggravate diabetic hyperglycemia.

SGK1 inhibitors may be similarly useful in the prophylactic, metaphylactic and curative treatment of tumor growth and several fibrosing diseases. Along those lines, the SGK1 inhibitor GSK650394 has been proposed for anticancer therapy [110].

Fig. 1

Regulation of SGK1 expression and activity

Fig. 2

Diagram summarizing the role of SGK1 in the development (red arrows) and consequences (blue arrows) of type 2 diabetes

Acknowledgements

Studies in the authors laboratory are funded by the Deutsche Forschungsgemeinschaft (GRK 1302, to F.L, GO709/4-4 to A.G.) and the National Institutes of Health (NIH to V.V.)

Annotated References

1. Firestone GL, Giampaolo JR, O'Keeffe BA. Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem. 2003;13:1–12. [PubMed]

2. Waldegger S, Barth P, Raber G, et al. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc Natl Acad Sci U S A. 1997;94:4440–4445. [PubMed]

3. Keller-Wood M, Powers MJ, Gersting JA, et al. Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation. Physiol Genomics. 2006;24:218–224. [PubMed]

4. Lang F, Bohmer C, Palmada M, et al. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev. 2006;86:1151–1178. [PubMed]

5. Kim SH, Kim KX, Raveendran NN, et al. Regulation of ENaC-mediated sodium transport by glucocorticoids in Reissner's membrane epithelium. Am J Physiol Cell Physiol. 2009;296:C544–C557. [PubMed]

6. Pondugula SR, Raveendran NN, Ergonul Z, et al. Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat. Physiol Genomics. 2006;24:114–123. [PubMed]

7. Zhong SX, Liu ZH. Expression patterns of Nedd4 isoforms and SGK1 in the rat cochlea. Acta Otolaryngol. 2008:1–5. [PubMed]

8. Brown SG, Gallacher M, Olver RE, et al. The regulation of selective and nonselective Na+ conductances in H441 human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2008;294:L942–L954. [PubMed]

9. Wirbelauer J, Schmidt B, Klingel K, et al. Serum and glucocorticoid-inducible kinase in pulmonary tissue of preterm fetuses exposed to chorioamnionitis. Neonatology. 2008;93:257–262. [PubMed]

10. Uawithya P, Pisitkun T, Ruttenberg BE, et al. Transcriptional profiling of native inner medullary collecting duct cells from rat kidney. Physiol Genomics. 2008;32:229–253. [PMC free article] [PubMed]

11. Inglis SK, Gallacher M, Brown SG, et al. SGK1 activity in Na+ absorbing airway epithelial cells monitored by assaying NDRG1-Thr346/356/366 phosphorylation. Pflugers Arch. 2009;457:1287–1301. [PubMed]

12. Arteaga MF, Alvarez dlR, Alvarez JA, et al. Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1. Mol Biol Cell. 2007;18:2072–2080. [PMC free article] [PubMed]

13. Raikwar NS, Snyder PM, Thomas CP. An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function. Am J Physiol Renal Physiol. 2008;295:F1440–F1448. [PubMed]

14. Simon P, Schneck M, Hochstetter T, et al. Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription. Cell Physiol Biochem. 2007;20:715–728. [PubMed]

15. Zhao B, Lehr R, Smallwood AM, et al. Crystal structure of the kinase domain of serum and glucocorticoid-regulated kinase 1 in complex with AMP PNP. Protein Sci. 2007;16:2761–2769. [PubMed]

16. Loffing J, Flores SY, Staub O. Sgk kinases and their role in epithelial transport. Annu Rev Physiol. 2006;68:461–490. [PubMed]

17. Kim MJ, Chae JS, Kim KJ, et al. Negative regulation of SEK1 signaling by serum- and glucocorticoid-inducible protein kinase 1. EMBO J. 2007;26:3075–3085. [PubMed]

18. Bertog M, Cuffe JE, Pradervand S, et al. Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome. J Physiol. 2008;586:459–475. [PubMed]

19. Fakitsas P, Adam G, Daidie D, et al. Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation. J Am Soc Nephrol. 2007;18:1084–1092. [PubMed]

20. Feroze-Zaidi F, Fusi L, Takano M, et al. Role and regulation of the serum- and glucocorticoid-regulated kinase 1 in fertile and infertile human endometrium. Endocrinology. 2007;148:5020–5029. [PubMed]

21. Belaiba RS, Djordjevic T, Bonello S, et al. The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. Circ Res. 2006;98:828–836. [PubMed]

22. Wolf SC, Schultze M, Risler T, et al. Stimulation of serum- and glucocorticoid-regulated kinase-1 gene expression by endothelin-1. Biochem Pharmacol. 2006;71:1175–1183. [PubMed]

23. Chang CT, Wu MS, Tian YC, et al. Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products. Nephrol Dial Transplant. 2007;22:722–731. [PubMed]

24. Pfau A, Grossmann C, Freudinger R, et al. Ca2+ but not H2O2 modulates GRE-element activation by the human mineralocorticoid receptor in HEK cells. Mol Cell Endocrinol. 2007;264:35–43. [PubMed]

25. Faroqui S, Sheriff S, Amlal H. Metabolic acidosis has dual effects on sodium handling by rat kidney. Am J Physiol Renal Physiol. 2006;291:F322–F331. [PubMed]

26. Nagase M, Yoshida S, Shibata S, et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol. 2006;17:3438–3446. [PubMed]

27. Shibata S, Nagase M, Yoshida S, et al. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49:355–364. [PubMed]

28. Conti B, Maier R, Barr AM, et al. Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine. Mol Psychiatry. 2007;12:167–189. [PubMed]

29. Wang Q, Zhang A, Li R, et al. High glucose promotes the CTGF expression in human mesangial cells via serum and glucocorticoid-induced kinase 1 pathway. J Huazhong Univ Sci Technolog Med Sci. 2008;28:508–512. [PubMed]

30. Vallon V, Wyatt AW, Klingel K, et al. SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment. J Mol Med. 2006;84:396–404. [PubMed]

31. Li L, Wingo CS, Xia SL. Downregulation of SGK1 by nucleotides in renal tubular epithelial cells. Am J Physiol Renal Physiol. 2007;293:F1751–F1757. [PubMed]

32. Poulin H, Filion C, Ladanyi M, et al. Serum- and glucocorticoid-regulated kinase 1 (SGK1) induction by the EWS/NOR1(NR4A3) fusion protein. Biochem Biophys Res Commun. 2006;346:306–313. [PubMed]

33. Cordas E, Naray-Fejes-Toth A, Fejes-Toth G. Subcellular location of serum- and glucocorticoid-induced kinase-1 in renal and mammary epithelial cells. Am J Physiol Cell Physiol. 2007;292:C1971–C1981. [PubMed]

34. Engelsberg A, Kobelt F, Kuhl D. The N-terminus of the serum- and glucocorticoid-inducible kinase Sgk1 specifies mitochondrial localization and rapid turnover. Biochem J. 2006;399:69–76. [PubMed]

35. Kobayashi T, 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. 1999;339:319–328. [PubMed]

36. Chen W, Chen Y, Xu BE, et al. Regulation of a Third Conserved Phosphorylation Site in SGK1. J Biol Chem. 2009;284:3453–3460. [PubMed]

37. Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: Signaling inputs, substrates and feedback mechanisms. Cell Signal. 2009 in press.

38. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1) Biochem J. 2008;416:375–385. [PubMed]

39. Hong F, Larrea MD, Doughty C, et al. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell. 2008;30:701–711. [PubMed]

40. Yan L, Mieulet V, Lamb RF. mTORC2 is the hydrophobic motif kinase for SGK1. Biochem J. 2008;416:e19–e21. [PubMed]

41. Bayascas JR, Wullschleger S, Sakamoto K, et al. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol Cell Biol. 2008;28:3258–3272. [PMC free article] [PubMed]

42. De Seigneux S, Leroy V, Ghzili H, et al. NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells. J Biol Chem. 2008;283:25671–25681. [PubMed]

43. Edinger RS, Lebowitz J, Li H, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem. 2009;284:150–157. [PubMed]

44. Hills CE, Squires PE, Bland R. Serum and glucocorticoid regulated kinase and disturbed renal sodium transport in diabetes. J Endocrinol. 2008;199:343–349. [PubMed]

45. Lee IH, Dinudom A, Sanchez-Perez A, et al. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 2007;282:29866–29873. [PubMed]

46. Lee IH, Campbell CR, Cook DI, et al. Regulation of epithelial Na+ channels by aldosterone: role of Sgk1. Clin Exp Pharmacol Physiol. 2008;35:235–241. [PubMed]

47. Naray-Fejes-Toth A, Boyd C, Fejes-Toth G. Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein. Am J Physiol Renal Physiol. 2008;295:F18–F26. [PubMed]

48. Pao AC, McCormick JA, Li H, et al. NH2 terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions. Am J Physiol Renal Physiol. 2007;292:F1741–F1750. [PubMed]

49. Vasquez MM, Castro R, Seidner SR, et al. Induction of serum- and glucocorticoid-induced kinase-1 (SGK1) by cAMP regulates increases in alpha-ENaC. J Cell Physiol. 2008;217:632–642. [PubMed]

50. Wang J, Knight ZA, Fiedler D, et al. Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport. Am J Physiol Renal Physiol. 2008;295:F843–F850. [PubMed]

51. Wielputz MO, Lee IH, Dinudom A, et al. (NDRG2) stimulates amiloride-sensitive Na+ currents in Xenopus laevis oocytes and fisher rat thyroid cells. J Biol Chem. 2007;282:28264–28273. [PubMed]

52. Seebohm G, Strutz-Seebohm N, Ureche ON, et al. Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels. Circ Res. 2008;103:1451–1457. [PubMed]

53. Boehmer C, Laufer J, Jeyaraj S, et al. Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination. Cell Physiol Biochem. 2008;22:591–600. [PubMed]

54. Bohmer C, Palmada M, Kenngott C, et al. Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid-inducible kinase isoforms SGK1 and SGK3. FEBS Lett. 2007;581:5586–5590. [PubMed]

55. Bergler T, Stoelcker B, Jeblick R, et al. High osmolality induces the kidney-specific chloride channel CLC-K1 by a serum and glucocorticoid-inducible kinase 1 MAPK pathway. Kidney Int. 2008;74:1170–1177. [PubMed]

56. Sato JD, Chapline MC, Thibodeau R, et al. Regulation of human cystic fibrosis transmembrane conductance regulator (CFTR) by serum- and glucocorticoid-inducible kinase (SGK1) Cell Physiol Biochem. 2007;20:91–98. [PubMed]

57. Shaw JR, Sato JD, VanderHeide J, et al. The role of SGK and CFTR in acute adaptation to seawater in Fundulus heteroclitus. Cell Physiol Biochem. 2008;22:69–78. [PubMed]

58. Arteaga MF, Coric T, Straub C, et al. A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons. Proc Natl Acad Sci U S A. 2008;105:4459–4464. [PubMed]

59. Fejes-Toth G, Frindt G, Naray-Fejes-Toth A, et al. Epithelial Na+ channel activation and processing in mice lacking SGK1. Am J Physiol Renal Physiol. 2008;294:F1298–F1305. [PubMed]

60. Fuster DG, Bobulescu IA, Zhang J, et al. Characterization of the regulation of renal Na+/H+ exchanger NHE3 by insulin. Am J Physiol Renal Physiol. 2007;292:F577–F585. [PMC free article] [PubMed]

61. Wang D, Zhang H, Lang F, et al. Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor. Am J Physiol Cell Physiol. 2007;292:C396–C404. [PMC free article] [PubMed]

62. Dieter M, Palmada M, Rajamanickam J, et al. Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB. Obes Res. 2004;12:862–870. [PubMed]

63. Grahammer F, Artunc F, Sandulache D, et al. Renal function of gene targeted mice lacking both SGK1 and SGK3. Am J Physiol Regul Integr Comp Physiol. 2006;290:R945–R950. [PubMed]

64. Shojaiefard M, Strutz-Seebohm N, Tavare JM, et al. Regulation of the Na(+), glucose cotransporter by PIKfyve and the serum and glucocorticoid inducible kinase SGK1. Biochem Biophys Res Commun. 2007;359:843–847. [PubMed]

65. Palmada M, Boehmer C, Akel A, et al. SGK1 kinase upregulates GLUT1 activity and plasma membrane expression. Diabetes. 2006;55:421–427. [PubMed]

66. Jeyaraj S, Boehmer C, Lang F, et al. Role of SGK1 kinase in regulating glucose transport via glucose transporter GLUT4. Biochem Biophys Res Commun. 2007;356:629–635. [PubMed]

67. Rajamanickam J, Palmada M, Lang F, et al. EAAT4 phosphorylation at the SGK1 consensus site is required for transport modulation by the kinase. J Neurochem. 2007;102:858–866. [PubMed]

68. Boehmer C, Palmada M, Klaus F, et al. The peptide transporter PEPT2 is targeted by the protein kinase SGK1 and the scaffold protein NHERF2. Cell Physiol Biochem. 2008;22:705–714. [PubMed]

69. Klaus F, Palmada M, Lindner R, et al. Up-regulation of hypertonicity-activated myoinositol transporter SMIT1 by the cell volume-sensitive protein kinase SGK1. J Physiol. 2008;586:1539–1547. [PubMed]

70. Ullrich S, Zhang Y, Avram D, et al. Dexamethasone increases Na+/K+ ATPase activity in insulin secreting cells through SGK1. Biochem Biophys Res Commun. 2007;352:662–667. [PubMed]

71. Zhang W, Xia X, Reisenauer MR, et al. Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha. J Clin Invest. 2007;117:773–783. [PMC free article] [PubMed]

72. Liang X, Butterworth MB, Peters KW, et al. An obligatory heterodimer of 14-3-3beta and 14-3-3epsilon is required for aldosterone regulation of the epithelial sodium channel. J Biol Chem. 2008;283:27418–27425. [PubMed]

73. Liang X, Peters KW, Butterworth MB, et al. 14-3-3 isoforms are induced by aldosterone and participate in its regulation of epithelial sodium channels. J Biol Chem. 2006;281:16323–16332. [PubMed]

74. Nagaki K, Yamamura H, Shimada S, et al. 14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels. Biochemistry. 2006;45:6733–6740. [PubMed]

75. Helms MN, Yu L, Malik B, et al. Role of SGK1 in nitric oxide inhibition of ENaC in Na+-transporting epithelia. Am J Physiol Cell Physiol. 2005;289:C717–C726. [PubMed]

76. Klaus F, Laufer J, Czarkowski K, et al. PIKfyve-dependent regulation of the Cl(−) channel ClC-2. Biochem Biophys Res Commun. 2009;381:407–411. [PubMed]

77. Strutz-Seebohm N, Shojaiefard M, Christie D, et al. PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cell Physiol Biochem. 2007;20:729–734. [PubMed]

78. Ring AM, Leng Q, Rinehart J, et al. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proc Natl Acad Sci U S A. 2007;104:4025–4029. [PubMed]

79. Leroy V, De Seigneux S, Agassiz V, et al. Aldosterone activates NF-kappaB in the collecting duct. J Am Soc Nephrol. 2009;20:131–144. [PubMed]

80. Tai DJ, Su CC, Ma YL, et al. SGK1 Phosphorylation of I{kappa}B Kinase {alpha} and p300 Up-regulates NF-{kappa}B Activity and Increases N-Methyl-D-aspartate Receptor NR2A and NR2B Expression. J Biol Chem. 2009;284:4073–4089. [PubMed]

81. Dehner M, Hadjihannas M, Weiske J, et al. Wnt signaling inhibits Forkhead box O3a-induced transcription and apoptosis through up-regulation of serum- and glucocorticoid-inducible kinase 1. J Biol Chem. 2008;283:19201–19210. [PubMed]

82. Martel JA, Michael D, Fejes-Toth G, et al. Melanophilin, a novel aldosterone-induced gene in mouse cortical collecting duct cells. Am J Physiol Renal Physiol. 2007;293:F904–F913. [PubMed]

83. Maier G, Palmada M, Rajamanickam J, et al. Upregulation of HERG channels by the serum and glucocorticoid inducible kinase isoform SGK3. Cell Physiol Biochem. 2006;18:177–186. [PubMed]

84. Taruno A, Niisato N, Marunaka Y. Intracellular calcium plays a role as the second messenger of hypotonic stress in gene regulation of SGK1 and ENaC in renal epithelial A6 cells. Am J Physiol Renal Physiol. 2008;294:F177–F186. [PubMed]

85. Amato R, Menniti M, Agosti V, et al. IL-2 signals through Sgk1 and inhibits proliferation and apoptosis in kidney cancer cells. J Mol Med. 2007;85:707–721. [PubMed]

86. Friedrich B, Weyrich P, Stancakova A, et al. Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies. PLoS ONE. 2008;3:e3506. [PMC free article] [PubMed]

87. Geranton SM, Morenilla-Palao C, Hunt SP. A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. J Neurosci. 2007;27:6163–6173. [PubMed]

88. Boini KM, Graf D, Kuhl D, et al. SGK1 dependence of insulin induced hypokalemia. Pflugers Arch. 2009;457:955–961. [PubMed]

89. Rotte A, Bhandaru M, Ackermann TF, et al. Role of PDK1 in regulation of gastric acid secretion. Cell Physiol Biochem. 2008;22:725–734. [PubMed]

90. Rotte A, Bhandaru M, Foller M, et al. APC sensitive gastric acid secretion. Cell Physiol Biochem. 2009;23:133–142. [PubMed]

91. Sandu C, Artunc F, Grahammer F, et al. Role of the serum and glucocorticoid inducible kinase SGK1 in glucocorticoid stimulation of gastric acid secretion. Pflugers Arch. 2007;455:493–503. [PubMed]

92. Shanmugam I, Cheng G, Terranova PF, et al. Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival. Cell Death Differ. 2007;14:2085–2094. [PubMed]

93. Campagna DR, Custodio AO, Antiochos BB, et al. Mutations in the serum/glucocorticoid regulated kinase 3 (Sgk3) are responsible for the mouse fuzzy (fz) hair phenotype. J Invest Dermatol. 2008;128:730–732. [PubMed]

94. Mauro TM, McCormick JA, Wang J, et al. Akt2 and SGK3 are both determinants of postnatal hair follicle development. FASEB J. 2009 [PubMed]

95. O'Rahilly S. Human obesity and insulin resistance: lessons from experiments of nature. Novartis Found Symp. 2007;286:13–20. [PubMed]

96. Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119:S10–S16. [PMC free article] [PubMed]

97. Schwab M, Lupescu A, Mota M, et al. Association of SGK1 gene polymorphisms with type 2 diabetes. Cell Physiol Biochem. 2008;21:151–160. [PubMed]

98. Ackermann TF, Boini KM, Volkl H, et al. SGK1-sensitive renal tubular glucose reabsorption in diabetes. Am J Physiol Renal Physiol. 2009;296:F859–F866. [PubMed]

99. Boini KM, Nammi S, Grahammer F, et al. Role of serum- and glucocorticoid-inducible kinase SGK1 in glucocorticoid regulation of renal electrolyte excretion and blood pressure. Kidney Blood Press Res. 2008;31:280–289. [PubMed]

100. Shi PP, Cao XR, Sweezer EM, et al. Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd\ Am J Physiol Renal Physiol. 2008;295:F462–F470. [PubMed]

101. Artunc F, Sandulache D, Nasir O, et al. Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone. Pflugers Arch. 2008;456:425–436. [PubMed]

102. Artunc F, Nasir O, Amann K, et al. Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome. Am J Physiol Renal Physiol. 2008;295:F1624–F1634. [PubMed]

103. Ackermann D, Mordasini D, Cheval L, et al. Sodium retention and ascites formation in a cholestatic mice model: role of aldosterone and mineralocorticoid receptor? Hepatology. 2007;46:173–179. [PubMed]

104. Nijenhuis T, Vallon V, van der Kemp AW, et al. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest. 2005;115:1651–1658. [PMC free article] [PubMed]

105. Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008;12:233–242. [PubMed]

106. Ziyadeh FN. Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy. Diabetes Res Clin Pract. 2008;82 Suppl 1:S38–S41. [PubMed]

107. Saad S, Stevens VA, Wassef L, et al. High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule. Kidney Int. 2005;68:985–997. [PubMed]

108. Stevens VA, Saad S, Chen XM, et al. The interdependence of EGF-R and SGK-1 in fibronectin expression in primary kidney cortical fibroblast cells. Int J Biochem Cell Biol. 2007;39:1047–1054. [PubMed]

109. Rexhepaj R, Boini KM, Huang DY, et al. Role of maternal glucocorticoid inducible kinase SGK1 in fetal programming of blood pressure in response to prenatal diet. Am J Physiol Regul Integr Comp Physiol. 2008;294:R2008–R2013. [PubMed]

110. Sherk AB, Frigo DE, Schnackenberg CG, et al. Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res. 2008;68:7475–7483. [PMC free article] [PubMed]