HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Vallon, V. Articles by Lang, F. Search for Related Content PubMed PubMed Citation Articles by Vallon, V. Articles by Lang, F.

NEW INVESTIGATOR AWARD IN REGULATORY AND INTEGRATIVE PHYSIOLOGY

Role of Sgk1 in salt and potassium homeostasis

¹Departments of Medicine and Pharmacology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California; ²Department of Clinical Neurobiology, University of Heidelberg; Departments of ³Pharmacology and ⁷Physiology I, University of Tübingen; ⁶Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Germany; ⁴Department of Pharmacology, University of Lausanne, Switzerland; ⁵Department of Physiology, Innsbruck Medical University, Austria

	ABSTRACT

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

 
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.

sodium reabsorption; potassium excretion; aldosterone; protein kinases; kidney

	ALDOSTERONE-INDUCED RENAL EXPRESSION AND IN VITRO ASSESSMENT OF SGK1 FUNCTION

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

 
The Sgk1 gene encodes a protein of 50 kDa that is a member of the "AGC" family of serine/threonine protein kinases. Its catalytic domain is 45–60% homologous to the catalytic domains of other serine/threonine protein kinases, such as Akt/protein kinase B, protein kinase A, and protein kinase C-zeta (71). Sgk1 was originally cloned as a glucocorticoid-sensitive gene (20, 71), and renal expression of Sgk1 was indeed shown to be sensitive to glucocorticoids (2, 10, 53). The mineralocorticoid aldosterone plays a major role in the maintenance of NaCl homeostasis during alterations in NaCl intake or extracellular fluid volume, and Sgk1 was shown to be upregulated by aldosterone (for review, see Refs. 20, 49, 63). With regard to in vivo observations, aldosterone treatment of rats was found to increase Sgk1 mRNA in whole kidney (10, 53). Furthermore, feeding a low-NaCl diet for 2 wk markedly increased renal Sgk1 mRNA, which was reversed by 24-h resalination (53). Vice versa, a high-NaCl diet reduced renal Sgk1 mRNA and protein by half (19). A more detailed analysis revealed that aldosterone increases the expression of Sgk1 mRNA (6, 13, 29) and protein (42) along the entire ASDN (summarized in Table 1). With acute single application, the increase in mRNA is seen within 30 min and the Sgk1 protein expression already decreases between 2 and 4 h, indicating a short half-life of Sgk1 (6, 42). In adrenalectomized rats, upregulation of Sgk1 protein precedes the aldosterone-induced apical translocation of ENaC into the membrane, consistent with a role of Sgk1 in ENaC activation (42). Notably, the rapid in vivo accumulation of Sgk1 and -ENaC after aldosterone injection takes place along the entire ASDN, whereas the translocation of -, -, -ENaC to the apical plasma membrane was restricted to its proximal portions, indicating that other factors that follow an axial gradient along the ASDN are, in addition. required for ENaC expression in the cell membrane (42). A similar and persistent effect on Sgk1 mRNA in the ASDN was seen in response to a low-NaCl diet (29).

	ROLE OF SGK1 IN NACL HOMEOSTASIS

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

 
Targeted disruption of -ENaC (31, 32), -ENaC (43), -ENaC (4), or the mineralocorticoid receptor (5) in mice was reported to be either not compatible with survival or leading to severe NaCl wasting, demonstrating their essential role for NaCl homeostasis. In comparison, on a standard NaCl diet, mice deficient for Sgk1 (sgk1–/–) developed normally, did not display any gross functional abnormalities, and histology was normal in all organs analyzed, including the kidney (72). Furthermore, no significant difference in blood pressure, glomerular filtration rate (GFR), or renal NaCl excretion have been detected between sgk1–/– and littermate wild-type mice (sgk1+/+). A hint for a renal defect on standard NaCl diet, however, was provided by the observation that sgk1–/– mice displayed modestly higher plasma aldosterone concentrations (72). Furthermore, plasma K⁺ concentrations under standard NaCl (and K⁺) diet, as determined in two separate studies, were either not significantly different between genotypes (30) or modestly increased in sgk1–/– vs. sgk1+/+ mice (4.7 vs. 4.1 mmol/l) (72). Thus, in the absence of Sgk1, normal NaCl reabsorption was achieved only by enhanced aldosterone release and/or enhanced aldosterone release served to stabilize plasma K⁺ concentrations reflecting an impaired renal ability to excrete K⁺ (see below).

In rats and mice on standard NaCl diet, expression of Sgk1 mRNA was localized to glomeruli, proximal tubule, the ASDN and very strongly to inner medullary collecting ducts (6, 13, 29, 42, 53). In comparison, no Sgk1 or very low levels of Sgk1 protein expression were detected under basal conditions in glomeruli, proximal tubule, or medullary collecting ducts, including the papilla in rat kidney (2). This dissociation between Sgk1 mRNA and protein expression may indicate some regulation on the translational level. Sgk1 is a cell volume- regulated 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. Absence of Sgk1 in mice, however, was found not to impair basal or maximal urinary concentrating ability (72), and thus the role of Sgk1 in the inner medulla remains to be determined. The latter observation further indicated that NaCl transport in the thick ascending limb as well as water transport in the collecting duct, which are both required for maximum urine concentration, are not significantly impaired in the absence of Sgk1.

In sharp contrast to the very mild renal phenotype under normal NaCl diet, restriction of dietary NaCl disclosed that the ability to upregulate renal NaCl reabsorption is significantly impaired in mice lacking Sgk1. This resulted in a significant net NaCl and body weight loss and occurred despite decreased blood pressure and GFR, which are system responses to an NaCl-losing kidney. Micropuncture experiments on the 3rd day of dietary NaCl restriction confirmed a decline of single nephron GFR in sgk1–/– mice and revealed a marked compensating increase of Na⁺ reabsorption in the proximal tubule (72). The nephron segment most susceptible to induction of ENaC expression and translocation to the apical membrane in response to a low-NaCl diet or aldosterone is the early ASDN, i.e., the late DCT and the CNT (41). Adult mice in general have no superficial glomeruli and therefore distal tubular loops on the kidney surface accessible to micropuncture mostly represent late DCT and CNT (27). Thus at least part of the aldosterone-sensitive segment is upstream to distal micropuncture sites in a normal mouse. This is of interest because fractional reabsorption of Na⁺ was enhanced in sgk1–/– mice in proximal tubule but was not different up to distal tubular sites, consistent with an Na⁺ transport defect in a segment including the early ASDN (72).

Electrophysiological analysis of isolated perfused cortical collecting duct on the 3rd day of dietary NaCl restriction revealed an amiloride-sensitive transepithelial potential difference in both sgk1+/+ and sgk1–/– mice; the potential difference, however, was significantly reduced in the absence of Sgk1. In accordance, in both sgk1+/+ and sgk1–/– mice, the -ENaC subunit was detected by immunohistochemistry in the luminal membrane of the ASDN, predominantly of the early ASDN (72). A blinded semiquantitative analysis, however, indicated that -ENaC abundance is significantly reduced in the luminal membrane of the early ASDN in mice lacking Sgk1. These studies demonstrate that Sgk1 participates in the upregulation of ENaC in the ASDN but that the kinase is not absolutely required for the insertion of ENaC into the apical membrane. Recent in vitro studies have shown that Sgk1 phosphorylates and presumably thereby inactivates the ubiquitin-ligase Nedd4–2 (15, 55). Consequently, Sgk1 may retard ubiquitination and subsequent degradation of ENaC (15, 55), resulting in an increase in ENaC protein abundance within the cell membrane. The observed increase in aldosterone plasma concentrations in the sgk1–/– mouse is expected to stimulate ENaC insertion into the cell membrane that might, at least partially, compensate for enhanced retrieval. Owing to the residual abundance of ENaC in the cell membrane of sgk1–/– mice, the defect in these mice is relatively mild under normal NaCl diet compared with that of -ENaC (31, 32)-, -ENaC (43)-, -ENaC (4)- or mineralocorticoid receptor-knockout mice (5). In response to dietary NaCl restriction, however, an Sgk1-dependent increase of ENaC in the apical membrane and likely an upregulation of basolateral Na⁺-K⁺-ATPase are required for an adequate increase of distal NaCl reabsorption and thus maintenance of NaCl homeostasis (Fig. 1).

View larger version (62K): [in this window] [in a new window]   Fig. 1. Proposed interaction between Sgk1, epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) in aldosterone-sensitive distal nephron. Aldosterone stimulates the expression of ENaC, ROMK, and Sgk1. Activation of Sgk1 (Sgk1a) requires phosphorylation of the kinase, which, in addition to other factors, can be induced by binding of insulin (Ins) or arginine vasopressin (AVP) to their basolateral receptors. Sgk1 is not absolutely required for insertion of ENaC or ROMK into the apical membrane, explaining the mild phenotype of Sgk1-deficient mice under standard NaCl and K+ diet. Sgk1-dependent upregulation of Na+ reabsorption, however, is required under reduced dietary NaCl intake as well as for upregulation of renal K+ excretion in response to increased dietary K+ intake. Sgk1a increases Na+ reabsorption by activating Na+-K+-ATPase and enhancing the abundance in the cell membrane of ENaC through inhibition of ubiquitin ligase Nedd4–2-mediated internalization of ENaC. Effects of Sgk1a on ENaC and Na+-K+-ATPase increase the electrical driving force for paracellular Cl– reabsorption as well as the electrochemical driving force for K+ secretion through ROMK. In addition, Sgk1 may enhance the abundance of ROMK in the apical membrane by synergizing with NHERF2. MR, mineralocorticoid receptor; PKA, protein kinase A; PDK, 3-phosphoinositide-dependent kinase.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Proposed role of Sgk1 in NaCl and K+ homeostasis and blood pressure regulation. Sgk1 affects total body NaCl through partially mediating effects of aldosterone on NaCl reabsorption in the aldosterone-sensitive distal nephron (ASDN). This influence of Sgk1 also contributes to the adaptation of K+ excretion in the ASDN in response to increased dietary K+ intake. Whether Sgk1, in addition to its role in renal NaCl reabsorption, enhances body NaCl and thus extracellular fluid volume (ECV) and arterial blood pressure through mediating effects of aldosterone on NaCl appetite and/or NaCl transport in other epithelia such as the colon remains to be established.

	ROLE OF SGK1 IN K+ HOMEOSTASIS

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

To test the importance of Sgk1 in vivo, renal excretion of K⁺ has been studied in mice lacking Sgk1 (30). These experiments demonstrated an impaired upregulation of renal K⁺ excretion in Sgk1-deficient mice in response to both acute and chronic K⁺ loading. The actual phenotypes observed, however, were strikingly different. In response to acute K⁺ loading, the defect became apparent as an attenuated increase in renal K⁺ excretion in sgk1–/– mice. In comparison, impaired upregulation of renal K⁺ excretion in response to chronic K⁺ loading was revealed by a renal K⁺ excretion in sgk1–/– mice that was not different from sgk1+/+ mice despite markedly increased plasma concentrations of both K⁺ and aldosterone in sgk1–/– mice, which are the major stimuli of renal K⁺ excretion.

A defect in ENaC and/or Na⁺-K⁺-ATPase rather than in ROMK as the dominant cause for the impaired upregulation of K⁺ excretion in Sgk1-deficient mice was indicated by the following two observations made under chronic K⁺ loading (30). First, immunohistochemistry did not show decreased but enhanced abundance of ROMK channel protein in the apical membrane of the ASDN of Sgk1-deficient mice during high K⁺ diet. This observation demonstrated that as for ENaC, Sgk1 is not required for insertion of ROMK into the apical membrane. The findings do not rule out an in vivo stimulating effect of Sgk1 on ROMK channel trafficking to the cell membrane because the lacking influence of Sgk1 could be more than compensated for by the observed hyperkalemia and/or enhanced aldosterone plasma concentrations if these influences enhance apical ROMK abundance partially independent of Sgk1 (Fig. 1). The observation nevertheless suggests that the impaired regulation of renal K⁺ elimination in Sgk1-deficient mice is the result of mechanisms other than impaired ROMK expression and ROMK channel trafficking to the cell membrane. Second, and supporting this assumption, electrophysiological experiments in the isolated perfused cortical collecting duct revealed a lower absolute and amiloride-sensitive transepithelial potential difference in mice deficient for Sgk1 in response to a high-K⁺ diet. This is consistent with a decreased activity of apical ENaC and/or basolateral Na⁺-K⁺-ATPase as the dominant cause for impaired upregulation of renal K⁺ elimination in Sgk1-deficient mice. A dominant defect in the apical K⁺ channel would be expected to increase rather than decrease the transepithelial potential difference in the collecting duct. The observation that renal K⁺ excretion in Sgk1-deficient mice on high-K⁺ diet reached similar values as K⁺ excretion in wild-type mice indicates that increases in plasma concentrations of K⁺ and aldosterone and a resulting enhanced apical abundance of ROMK compensate for the defect in apical ENaC and/or basolateral Na⁺-K⁺-ATPase (Fig. 2).

Perspectives

Data obtained in Sgk1-deficient mice demonstrate that the regulation of NaCl and K⁺ homeostasis involve Sgk1. More recently, the two isoforms, Sgk2 and Sgk3, have been cloned (35). The renal expression of these two isoforms appears 1) significantly lower than Sgk1 (2) and 2) unresponsive to cortisol or aldosterone (2), but both have been shown to stimulate ENaC activity in Xenopus oocytes (21). It remains to be determined whether they partly compensate for a lack in Sgk1. In addition to the ASDN, the kidney constitutively expresses Sgk1 in glomeruli, thick ascending limb, and possibly early distal convoluted tubule (Table 1), i.e., sites that are not typically considered aldosterone sensitive, although evidence for aldosterone-induced expression of the Na⁺-Cl^–-cotransporter NCC in the early distal convoluted tubule has been reported in rat (45). The functions of Sgk1 at these sites remain to be determined.

Expression studies in Xenopus oocytes demonstrated that Sgk1 could activate a K⁺ channel that is formed by KCNQ1 and its regulatory subunit KCNE1 (17). In the S2 and S3 segments of proximal tubule of the kidney, this K⁺ channel serves to prevent membrane depolarization during electrogenic reabsorption of Na⁺ with glucose (58). Normally, filtered glucose is almost completely reabsorbed in the proximal tubule. Apical entry is accomplished by electrogenic low-affinity Na⁺-glucose cotransporter SGLT2 in the S1 segment and higher affinity SGLT1 in the later S2 and S3 segments. Recent coexpression studies in Xenopus oocytes showed that Sgk1 can activate SGLT1 (16) (whether Sgk1 similarly affects SGLT2 is not known). Similar to what was described for the regulation of ENaC, SGLT1 is regulated by the ubiquitin ligase Nedd4–2 (16). Activation of Sgk1 leads to phosphorylation and thus inhibition of Nedd4–2 binding to its target protein, leading to impaired clearance of SGLT1 protein from the cell membrane. Thus stimulation of Sgk1 enhanced glucose transport by increasing SGLT1 protein abundance in the cell membrane in vitro (16). Whether Sgk1 regulates and coordinates KCNQ1/KCNE1 and SGLT1 in vivo is unclear, and as noted above, Sgk1 mRNA, but not Sgk1 protein, was detected in proximal tubule under basal conditions (2, 42). Clearly, it is possible that under certain conditions the expression of Sgk1 can be stimulated in nephron segments that do not express Sgk1 protein under basal conditions, or the Sgk1 protein level is too low for detection. Similar thoughts apply to a proposed role of Sgk1 in proximal tubule regulation of both the Na⁺/H⁺ exchanger NHE3 (75), which controls about 30% of Na⁺ and fluid reabsorption at this site (62), as well as the electrogenic Na⁺- coupled dicarboxylate transporter NaDC-1 (9). The proposed regulation of these two transporters by Sgk1 through a mechanism involving NHERF-2 is based on in vitro expression studies and its relevance remains to be confirmed in vivo.

Whereas aldosterone can stimulate the expression of Sgk1, the latter has to be phosphorylated for activation (Fig. 1). Phosphorylation of Sgk1 involves signaling cascades, including phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinases PDK1 and PDK2 (7, 34, 48). Furthermore, aldosterone itself may promote Sgk1 activation by directly increasing the cellular concentrations of phosphatidylinositol [3,4,5]-trisphosphate, but the involved mechanisms are not known (8). Other pathways independent of phosphatidylinositol [3,4,5]-trisphosphate such as cell–cell and matrix interactions and phosphorylation by protein kinase A (PKA) have also been found to activate Sgk1 (37, 50, 52). Reported PDK-dependent activators of Sgk1 include insulin and growth factors such as insulin-like growth factor (25, 34, 50). Further studies demonstrated a role of Sgk1 in the stimulating effects of insulin and the PKA-activator AVP on Na⁺ transport in the A6 model renal cell line (3, 18, 69). Thus Sgk1 may integrate the influences of aldosterone and factors such as insulin, other growth factors, or AVP on renal NaCl reabsorption (18, 69) (see Fig. 1). Considering that insulin can increase renal NaCl reabsorption in the distal nephron and that hyperinsulinemia and enhanced growth hormone levels can be associated with hypertension, it seems possible that Sgk1 mediates these effects on the kidney and thus on blood pressure. Likewise, a possible role of Sgk1 in glucocorticoid-induced renal NaCl retention and arterial hypertension awaits support by functional studies. This also applies to the observation that peroxisome proliferators-activated receptor gamma (PPAR) activation enhances cell surface expression of ENaC via upregulation of Sgk1 in human collecting duct cells (28). Activators of PPAR are used as antidiabetic drugs, and adverse side effects include volume retention that may involve Sgk1. Furthermore, enhanced expression of Sgk1 was associated with diabetic nephropathy and fibrosis (36, 39). High glucose concentrations can induce the expression of Sgk1 (39), and a hot spot in the early diabetic kidney exposed to and responding to high glucose as well as the site of major changes in NaCl transport and NaCl transport regulation in early diabetes is the proximal tubule (57, 59, 61). Clearly, the roles of Sgk1 in the early diabetic kidney, diabetic nephropathy, and fibrosis remain to be established, and, as for the above aspects, studies in Sgk1-deficient mice are expected to provide significant insights.

A potential role for impaired regulation of Sgk1 in NaCl-sensitive hypertension was suggested from studies in Dahl rats: whereas a high-NaCl diet lowered renal expression of Sgk1 and did not affect blood pressure in Sprague-Dawley rats, the NaCl-sensitive Dahl rats showed an increased renal expression of Sgk1 associated with the increase in blood pressure (19). Unfortunately, the nephron site of enhanced Sgk1 expression was not determined. A significance of Sgk1 for regulation of arterial blood pressure in humans was indicated by the fact that certain polymorphisms of the Sgk1 gene correlate with enhanced blood pressure in twin studies (11). Moreover, the same polymorphisms are associated with increased body mass index (16), which may result from the potential stimulation by Sgk1 of the Na⁺-glucose transporter SGLT1 in the intestine (16). However, at present it is not clear how the polymorphisms influence the expression or function of Sgk1. Further studies are required to establish the functional consequences of these polymorphisms for NaCl, K⁺, or glucose transport or induction of NaCl appetite and, most importantly, whether polymorphisms of the Sgk1 gene and/or enhanced activities of Sgk1 correlate with the occurrence of arterial hypertension in humans, which would underline the potential of Sgk1 as an attractive target for novel therapeutic strategies.

	GRANTS

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

 
Studies by the authors were supported by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Center for Interdisciplinary Clinical Research) 01 KS 9602 and Deutsche Forschungsgemeinschaft (Va 118/7–2, La 315/4–4, La 315/5–1).

	FOOTNOTES

 

Address for reprint requests and other correspondence: V. Vallon, Depts. of Medicine and Pharmacology, Univ. of California San Diego & VAMC, 3350 La Jolla Village Drive (9151), San Diego, CA 92161 (E-mail: vvallon{at}ucsd.edu)

	REFERENCES

TOP ABSTRACT ALDOSTERONE-INDUCED RENAL... ROLE OF SGK1 IN... ROLE OF SGK1 IN... GRANTS REFERENCES

 

1. Alvarez de la Rosa DA, Zhang P, Náray-Fejes-Tóth A, Fejes-Tóth 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.[Abstract/Free Full Text]
2. Alvarez de la Rosa D, Coric T, Todorovic N, Shao D, Wang T, and Canessa CM. Distribution and regulation of expression of serum- and glucocorticoid-induced kinase-1 in the rat kidney. J Physiol 551: 455–466, 2003.[Abstract/Free Full Text]
3. Alvarez de la Rosa D and Canessa CM. Role of SGK in hormonal regulation of epithelial sodium channel in A6 cells. Am J Physiol Cell Physiol 284: C404–C414, 2003.[Abstract/Free Full Text]
4. Barker PM, Nguyen MS, Gatzy JT, Grubb B, Norman H, Hummler E, Rossier B, Boucher RC, and Koller B. Role of ENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism. J Clin Invest 102:1634–1640, 1998.[ISI][Medline]
5. 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.[Abstract/Free Full Text]
6. 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.[Abstract/Free Full Text]
7. Biondi RM, Kieloch A, Currie RA, Deak M, and Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J 20: 4380–4390, 2001.[CrossRef][ISI][Medline]
8. 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.[Abstract/Free Full Text]
9. Boehmer C, Embark HM, Bauer A, Palmada M, Yun CH, Weinman EJ, Endou H, Cohen P, Lahme S, Bichler KH, and Lang F. Stimulation of renal Na⁺ dicarboxylate cotransporter 1 by Na⁺/H⁺ exchanger regulating factor 2, serum and glucocorticoid inducible kinase isoforms, and protein kinase B. Biochem Biophys Res Commun 313: 998–1003, 2004.[CrossRef][ISI][Medline]
10. 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.[CrossRef][ISI][Medline]
11. Busjahn A, Aydin A, Uhlmann R, Feng Y, Luft FC, and Lang F. Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure. Hypertension 40: 256–260, 2002.[Abstract/Free Full Text]
12. Chang SS, Grunder S, Hanukoglu A, Rosler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, and Lifton RP. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet 12:248–253, 1996.[CrossRef][ISI][Medline]
13. Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, and Pearce D. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci USA 96: 2514–2519, 1999.[Abstract/Free Full Text]
14. Chen S, McCormick JA, Prabaker K, Wang J, Pearce D, and Gardner DG. Sgk1 mediates osmotic induction of NPR-A gene in rat inner medullary collecting duct cells. Hypertension 43: 866–871, 2004.[Abstract/Free Full Text]
15. 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.[CrossRef][ISI][Medline]
16. Dieter M, Palmada M, Rajamanickam J, Aydin A, Busjahn A, Boehmer C, Luft FC, and Lang F. Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4–2 and kinases SGK1, SGK3, and PKB. Obes Res 12: 862–870, 2004.[ISI][Medline]
17. Embark HM, Bohmer C, Vallon V, Luft F, and Lang F. Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms. Pflügers Arch 445: 601–606, 2003.[ISI][Medline]
18. Faletti CJ, Perrotti N, Taylor SI, and Blazer-Yost BL. Sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na⁺ transport. Am J Physiol Cell Physiol 282: C494–C500, 2002.[Abstract/Free Full Text]
19. Farjah M, Roxas BP, Geenen DL, and Danziger RS. Dietary salt regulates renal SGK1 abundance: relevance to salt sensitivity in the Dahl rat. Hypertension 41: 874–878, 2003.[Abstract/Free Full Text]
20. Firestone GL, Giampaolo JR, and O'Keeffe BA. Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (Sgk) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13: 1–12, 2003.[ISI][Medline]
21. Friedrich B, Feng Y, Cohen P, Risler T, Vandewalle A, Broer S, Wang J, Pearce D, and Lang F. The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na⁺ channel ,,-ENaC. Pflügers Arch 445: 693–696, 2003.[ISI][Medline]
22. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, and Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289: 119–123, 2000.[Abstract/Free Full Text]
23. Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, and Lifton RP. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet 19: 279–281, 1998.[CrossRef][ISI][Medline]
24. Guyton AC. Physiological regulation of arterial pressure. Am J Cardiol 8: 401–407, 1961.[CrossRef][ISI][Medline]
25. 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.[Abstract/Free Full Text]
26. Henke G, Setiawan I, Böhmer C, and Lang F. Activation of Na⁺,K⁺ATPase by the serum and glucocorticoid dependent kinase (SGK) isoforms. Kidney Blood Press Res 25: 370–374, 2002.[CrossRef][ISI][Medline]
27. Hoenderop JGJ, van Leeuwen JPTM, van der Eerden BCJ, Kersten FFJ, van der Kemp AWCM, Merillat AM, Waarsing JH, Rossier BC, Vallon V, Hummler E, and Bindels RJM. Renal Ca²⁺ wasting, hyperabsorption and reduced bone thickness in mice lacking TRPV5. J Clin Invest 112: 1906–1914, 2003.[CrossRef][ISI][Medline]
28. Hong G, Lockhart A, Davis B, Rahmoune H, Baker S, Ye L, Thompson P, Shou Y, O'Shaughnessy K, Ronco P, and Brown J. PPAR activation enhances cell surface ENaC via up-regulation of SGK1 in human collecting duct cells. FASEB J 17: 1966–1968, 2003.[Abstract/Free Full Text]
29. Hou J, Speirs HJ, Seckl JR, and Brown RW. Sgk1 gene expression in kidney and its regulation by aldosterone: spatio-temporal heterogeneity and quantitative analysis. J Am Soc Nephrol 13: 1190–1198, 2002.[Abstract/Free Full Text]
30. Huang DY, Wulff P, Voelkl H, Loffing J, Richter K, Kuhl D, Lang F, and Vallon V. Impaired regulation of renal K⁺ elimination in the sgk1-knockout mouse. J Am Soc Nephrol 15: 885–891, 2004.[Abstract/Free Full Text]
31. Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, Schmidt A, Boucher R, and Rossier BC. Early death due to defective neonatal lung liquid clearance in -ENaC-deficient mice. Nat Genet 12: 325–328, 1996.[CrossRef][ISI][Medline]
32. Hummler E, Barker P, Talbot C, Wang Q, Verdumo C, Grubb B, Gatzy J, Burnier M, Horisberger JD, Beermann F, Boucher R, and Rossier BC. A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism. Proc Natl Acad Sci USA 94: 11710–11715, 1997.[Abstract/Free Full Text]
33. Kamynina E and Staub O. Concerted action of ENaC, Nedd4–2, and Sgk1 in transepithelial Na⁺ transport. Am J Physiol Renal Physiol 283: F377–F387, 2002.[Abstract/Free Full Text]
34. 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.[CrossRef][ISI][Medline]
35. Kobayashi T, Deak M, Morrice N, and Cohen P. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J 344: 189–197, 1999.[CrossRef][ISI][Medline]
36. Kumar JM, Brooks DP, Olson BA, and Laping NJ. Sgk, a putative serine/threonine kinase, is differentially expressed in the kidney of diabetic mice and humans. J Am Soc Nephrol 10: 2488–2494, 1999.[Abstract/Free Full Text]
37. Lang F and Cohen P. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Science's STKE 108/RE17: 1–11, 2001.
38. Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Böhmer C, and Vallon V. Regulation of channels by the serum and glucocorticoid-inducible kinase—implications for transport, excitability and cell proliferation. Cell Physiol Biochem 13: 41–50, 2003.[CrossRef][ISI][Medline]
39. Lang F, Klingel K, Wagner CA, Stegen C, Wärntges S, Friedrich B, Lanzendörfer M, Melzig J, Moschen I, Steuer S, Waldegger S, Sauter M, Paulmichl M, Gerke V, Risler T, Gamba G, Capasso G, Kandolf R, Hebert SC, Massry SG, and Bröer S. Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabetic nephropathy. Proc Natl Acad Sci USA 97: 8157–8162, 2000.[Abstract/Free Full Text]
40. Loffing J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JG, Bindels RJ, and Kaissling B. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal Physiol 281: F1021–F1027, 2001.[Abstract/Free Full Text]
41. 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.[Abstract/Free Full Text]
42. Loffing J, Zecevic M, Féraille 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.[Abstract/Free Full Text]
43. McDonald FJ, Yang B, Hrstka RF, Drummond HA, Tarr DE, McCray PB Jr, Stokes JB, Welsh MJ, and Williamson RA. Disruption of the beta subunit of the epithelial Na⁺ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype. Proc Natl Acad Sci USA 96: 1727–1731, 1999.[Abstract/Free Full Text]
44. Náray-Fejes-Tóth A, Canessa C, Cleaveland ES, Aldrich G, and Fejes-Tóth G Sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial Na⁺ channels. J Biol Chem 274: 16973–16978, 1999.[Abstract/Free Full Text]
45. Nielsen J, Kwon TH, Masilamani S, Beutler K, Hager H, Nielsen S, and Knepper MA. Sodium transporter abundance profiling in kidney: effect of spironolactone. Am J Physiol Renal Physiol 283: F923–F933, 2002.[Abstract/Free Full Text]
46. Palmada M, Embark HM, Wyatt AW, Bohmer C, and Lang F. Negative charge at the consensus sequence for the serum- and glucocorticoid-inducible kinase, SGK1, determines pH sensitivity of the renal outer medullary K⁺ channel, ROMK1. Biochem Biophys Res Commun 307: 967–972, 2003.[CrossRef][ISI][Medline]
47. Palmada M, Embark HM, Yun C, Bohmer C, and Lang F. Molecular requirements for the regulation of the renal outer medullary K⁺ channel ROMK1 by the serum- and glucocorticoid-inducible kinase SGK1. Biochem Biophys Res Commun 311: 629–634, 2003.[CrossRef][ISI][Medline]
48. 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.[CrossRef][ISI][Medline]
49. Pearce D. SGK1 regulation of epithelial sodium transport. Cell Physiol Biochem 13: 13–20, 2003.[CrossRef][ISI][Medline]
50. Perrotti N, He RA, Phillips SA, Haft CR, and Taylor SI. Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin. J Biol Chem 276: 9406–9412, 2001.[Abstract/Free Full Text]
51. Setiawan I, Henke G, Feng Y, Böhmer C, Vasilets LA, Schwarz W, and Lang F. Stimulation of Xenopus oocyte Na⁺,K⁺ATPase by the serum, and glucocorticoid-dependent kinase sgk1. Pflügers Arch 444: 426–431, 2002.[CrossRef][ISI][Medline]
52. Shelly C and Herrera R. Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J Cell Sci 115: 1985–1993, 2002.[Abstract/Free Full Text]
53. 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.[Abstract/Free Full Text]
54. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR Jr, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, and Lifton RP. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79: 407–414, 1994.[CrossRef][ISI][Medline]
55. Snyder PM, Olson DR, Thomas BC. SGK modulates Nedd4–2-mediated inhibition of ENaC. J Biol Chem 277: 5–8, 2002.[Abstract/Free Full Text]
56. Strautnieks SS, Thompson RJ, Gardiner RM, Chung E. A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Nat Genet 13: 248–250, 1996.[CrossRef][ISI][Medline]
57. Vallon V, Blantz RC, and Thomson SC. Glomerular hyperfiltration and the salt paradox in early diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 14: 530–537, 2003.[Abstract/Free Full Text]
58. Vallon V, Grahammer F, Richter K, Bleich M, Lang F, Barhanin J, Volkl H, and Warth R. Role of KCNE1-dependent K⁺ fluxes in mouse proximal tubule. J Am Soc Nephrol 12: 2003–2011, 2001.[Abstract/Free Full Text]
59. Vallon V, Huang DY, Deng A, Richter K, Blantz RC, and Thomson S. Salt-sensitivity of proximal reabsorption alters macula densa salt and explains the paradoxical effect of dietary salt on glomerular filtration rate in diabetes mellitus. J Am Soc Nephrol 13: 1865–1871, 2002.[Abstract/Free Full Text]
60. Vallon V, Huang DY, Wulff P, Kuhl D, and Lang F. DOCA-induced salt appetite is attenuated in mice lacking sgk1 (Abstract). FASEB J 18: A298, 2004.
61. Vallon V, Richter K, Blantz RC, Thomson S, and Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 10: 2569–2576, 1999.[Abstract/Free Full Text]
62. Vallon V, Schwark JR, Richter K, and Hropot M. Role of Na⁺/H⁺ exchanger NHE3 in nephron function: micropuncture studies with S3226, an inhibitor of NHE3. Am J Physiol Renal Physiol 278: F375–F379, 2000.[Abstract/Free Full Text]
63. Verrey F, Loffing J, Zecevic M, Heitzmann D, and Staub O. SGK1: aldosterone-induced relay of Na⁺ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 13: 21–28, 2003.[CrossRef][ISI][Medline]
64. Vuagniaux G, Vallet V, Jaeger NF, Hummler E, and Rossier BC. Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol 120: 191–201, 2002.[Abstract/Free Full Text]
65. Wade JB, Welling P, Donowitz M, Shenolikar S, and Weinman EJ. Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. Am J Physiol Cell Physiol 280: C192–C198, 2001.[Abstract/Free Full Text]
66. 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.[Abstract/Free Full Text]
67. Waldegger S, Barth P, Raber G, and Lang F. 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 USA 94: 4440–4445, 1997.[Abstract/Free Full Text]
68. Wagner CA, Ott M, Klingel K, Beck S, Melzig J, Friedrich B, Wild NK, Bröer S, Moschen I, Albers A, Waldegger S, Tümler B, Egan E, Geibel JP, Kandolf R, and Lang F. Effects of serine/threonine kinase SGK1 on the epithelial Na+ channel (ENaC) and CFTR. Cell Physiol Biol 11: 209–218, 2001.
69. 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.[Abstract/Free Full Text]
70. Wang W. Regulation of the ROMK channel: interaction of the ROMK with associate proteins. Am J Physiol Renal Physiol 277: F826–F831, 1999.[Abstract/Free Full Text]
71. 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/Free Full Text]
72. Wulff P, Vallon V, Huang DY, Volkl H, Yu F, Richter K, Jansen M, Schlunz M, Klingel K, Loffing J, Kauselmann G, Bosl MR, Lang F, and Kuhl D. Impaired renal Na⁺ retention in the sgk1-knockout mouse. J Clin Invest 110: 1263–1268, 2002.[CrossRef][ISI][Medline]
73. Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, and Hebert SC. Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am J Physiol Renal Physiol 273: F739–F748, 1997.[Abstract/Free Full Text]
74. Yoo D, Kim BY, Campo C, Nance L, King A, Maouyo D, and Welling PA. Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. J Biol Chem 278: 23066–23075, 2003.[Abstract/Free Full Text]
75. Yun CC, Chen Y, and Lang F. Glucocorticoid activation of Na⁺/H⁺ exchanger isoform 3 revisited. The roles of SGK1 and NHERF2. J Biol Chem 277: 7676–7683, 2002.[Abstract/Free Full Text]
76. Yun CC, Palmada M, Embark HM, Feng Y, Henke G, Setiawan I, Boehmer C, Weinmann EJ, Korbmacher C, Cohen P, Pearce D, and Lang F. The serum and glucocorticoid inducible kinase SGK1 and the Na⁺/H⁺ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K⁺ channel ROMK1. J Am Soc Nephrol 13: 2823–2830, 2002.[Abstract/Free Full Text]
77. Zecevic M, Heitzmann D, Camargo SM, and Verrey F. SGK1 increases Na,K-ATP cell-surface expression and function in Xenopus laevis oocytes. Pflügers Arch 448: 29–35, 2004.[CrossRef][ISI][Medline]

This article has been cited by other articles:

				E. Cordas, A. Naray-Fejes-Toth, and G. Fejes-Toth Subcellular location of serum- and glucocorticoid-induced kinase-1 in renal and mammary epithelial cells Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1971 - C1981. [Abstract] [Full Text] [PDF]

				F. Lang, C. Bohmer, M. Palmada, G. Seebohm, N. Strutz-Seebohm, and V. Vallon (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms. Physiol Rev, October 1, 2006; 86(4): 1151 - 1178. [Abstract] [Full Text] [PDF]

				H. Abriel and O. Staub Ubiquitylation of Ion Channels Physiology, December 1, 2005; 20(6): 398 - 407. [Abstract] [Full Text] [PDF]

				E. Hummler and V. Vallon Lessons from Mouse Mutants of Epithelial Sodium Channel and Its Regulatory Proteins J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3160 - 3166. [Abstract] [Full Text] [PDF]

				J. D. Stockand Preserving salt: in vivo studies with Sgk1-deficient mice define a modern role for this ancient protein Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R1 - R3. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Vallon, V. Articles by Lang, F. Search for Related Content PubMed PubMed Citation Articles by Vallon, V. Articles by Lang, F. <