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Angaben zur Quelle [Bearbeiten]

Autor     Krishna Murthy Boini
Titel    Role of SGK1 in Salt Sensitivity of Blood Pressure and Peripheral Glucose Uptake: Studies in Knockout Mice
Ort    Tübingen
Jahr    2006
Anmerkung    DISSERTATION der Fakultät für Chemie und Pharmazie der Eberhard-Karls-Universität Tübingen
URL    http://d-nb.info/983661235/34

Literaturverz.   

no
Fußnoten    no
Fragmente    15


Fragmente der Quelle:
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1.3.2. The SGK1 Isoforms SGK2 and SGK3

There are two paralogs of SGK1, SGK2 and SGK3/CISK, which share 80% amino acid identity with SGK1 and with each other in their catalytic domains (Kobayashi T. et al., (1999) Biochem J; Liu D. et al., (2000) Curr Biol; Dai F. et al., (1999) Genomics).

1.2 The SGK1 Isoforms SGK2 and SGK3

There are two paralogs of SGK1, SGK2 and SGK3/CISK, which share 80% amino acid identity with SGK1 and with each other in their catalytic domains (Kobayashi et al., 1999; Liu et al., 2000; Dai et al., 1999).

Anmerkungen

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[2.] Dsa/Fragment 027 04 - Diskussion
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The three enzymes differ in the region N-terminal of the C-terminal catalytic domain: SGK2 contains a relatively short N terminus (98 amino acids), with no discernable domain, whereas SGK3 has a longer N terminus (162 amino acids) comprising a phox homology (PX) domain (Xu J. et al., (2001) Cell Biol).

PX domains were originally found as conserved domains in the p40phox and p47phox subunits of the neutrophil NADPH oxidase (phox) superoxide-generating complex (Ponting CP., (1996) Protein Sci). These domains are part of many proteins involved in intracellular protein trafficking, such as the sorting nexins. PX domains are phosphoinositide-binding domains that appear to be important for localization of these proteins to membranes (especially endosomes) enriched in phosphoinositides. In this respect, these domains resemble other domains such as the pleckstrin homology (PH), FYFE, FERM and ENTH domains. PKB/Akt contains a PH domain in its N terminus, which is important for PKB/Akt activation by phosphoinositide-3 kinases (PI-3Ks). This domain enables the colocalization with the 3- phosphoinositide-dependent protein kinase-1 (PDK1), which is known to phosphorylate and activate PKB/Akt. Similarly, SGK3’s PX domain is involved in SGK3 localization and activity: It is necessary for phosphoinositide binding, endosomal localization, and proper kinase activity. Moreover, structural studies indicate that it may play a role in dimerization of the kinase. With respect to their physiological role(s), it has been shown in vitro that both the SGK2 and SGK3 enzymes have the same phosphorylation consensus as SGK1 (and PKB/Akt), namely R-X-R-X-X-(S/T). It is likely, however, that other factors, such as surrounding amino acids, subcellular localization, or cofactors are important for the specificity of and functional differences between the enzymes. For example, in Xenopus A6 cells, only SGK1 and not the coexpressed PKB modulates the activity of the epithelial Na+ channel (ENaC) (Arteaga MF. et al., (2005) Am J Physiol Renal Physiol).

The role of SGK2 has mainly been studied in heterologous expression systems such as Xenopus laevis oocytes or HEK293 cells and with respect to numerous transport and channel proteins. These studies revealed that SGK2 can stimulate the activity of K+ channels such as the voltage- gated K+ channel Kv1.3 (Gamper et al., (2002) Pflügers Arc,; Henke et al., (2004) J Cell Physiol), Na+-K+-ATPase (Henke G. et al., (2002) Kidney Blood Press Res), KCNE1 (Embark et al., (2003) Pflügers Arch), ENaC (Friedrich et al., (2003) Pflügers Arch), the glutamate transporter EEAT4 (Böhmer et al., (2004) Biochem Biophys Res Commun), and the glutamate receptors GluR6 (Strutz-Seebohm et al., (2005) J Physiol) and GluR1 (Strutz-Seebohm et al., (2005a) J Physiol). All of these transport proteins are also stimulated in the same cellular systems by SGK1, SGK3, and/or PKB; hence, the physiological relevance of these findings has to be considered with caution. To define more precisely the role of SGK2, it will be necessary to carry out additional studies, using more relevant cell or animal systems and knocking down SGK2 by either RNA interference protocols or by gene inactivation. SGK3/CISK, which is better characterized than SGK2, was identified in a screen for antiapoptotic genes (Liu et al., (2000) Curr Biol) and found to act downstream of the PI-3K pathway and in parallel with PKB/Akt. Moreover, it was demonstrated to phosphorylate and inhibit Bad (a proapoptotic protein) and FKHRL1, a proapoptotic transcription factor. Knockout (ko) mice have been generated; these mice are viable and fertile and have normal Na+ handling and glucose tolerance, as opposed to the KO mice of SGK1 or PKB/Akt2 (McCormick et al., (2004) Mol Biol Cell; Garofalo et al., (2003) J Clin Invest; Wulff et al., (2002) J Clin Invest). However, they display after birth a defect in hair follicle development, a defect preceded by disturbances in the β-catenin/Lef1 gene regulation (McCormick et al., (2004) Mol Biol Cell).

The three enzymes differ in the region N-terminal of the C-terminal catalytic domain: SGK2 contains a relatively short N terminus (98 amino

[page 11]

acids), with no discernable domain, whereas SGK3 has a longer N terminus (162 amino acids) comprising a phox homology (PX) domain (Xu et al., 2001). PX domains were originally found as conserved domains in the p40phox and p47phox subunits of the neutrophil NADPH oxidase (phox) superoxide-generating complex (Ponting 1996). These domains are part of many proteins involved in intracellular protein trafficking, such as the sorting nexins (Worby and Dixon 2002). PX domains are phosphoinositide-binding domains that appear to be important for localization of these proteins to membranes (especially endosomes) enriched in phosphoinositides. In this respect, these domains resemble other domains such as the pleckstrin homology (PH), FYFE, FERM and ENTH domains. PKB/Akt contains a PH domain in its N terminus, which is important for PKB/Akt activation by phosphoinositide-3 kinases (PI-3Ks). This domain enables the colocalization with the 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which is known to phosphorylate and activate PKB/Akt. Similarly, SGK3’s PX domain is involved in SGK3 localization and activity: It is necessary for phosphoinositide binding, endosomal localization, and proper kinase activity (Xu et al., 2001; Liu et al., 2000). Moreover, structural studies indicate that it may play a role in dimerization of the kinase (Xing et al., 2004). With respect to their physiological role(s), it has been shown in vitro that both the SGK2 and SGK3 enzymes have the same phosphorylation consensus as SGK1 (and PKB/Akt), namely R-X-R-X-X-(S/T) (Kobayashi et al., 1999). It is likely, however, that other factors, such as surrounding amino acids, subcellular localization, or cofactors are important for the specificity of and functional differences between the enzymes. For example, in Xenopus A6 cells, only SGK1 and not the coexpressed PKB modulates the activity of the epithelial Na+ channel (ENaC) (Artega et al., 2005). The role of SGK2 has mainly been studied in heterologous expression systems such as Xenopus laevis oocytes or HEK293 cells and with respect to numerous transport and channel proteins. These studies revealed that SGK2 can stimulate the activity of K+ channels such as the voltage- gated K+ channel Kv1.3 (Gamper et al., 2002; Henke et al., 2004), Na+,K+-ATPase (Henke et al., 2002), KCNE1 (Embark et al., 2003), ENaC (Friedrich et al., 2003), the glutamate transporter EEAT4 (Bohmer et al., 2004), and the glutamate receptors GluR6 (Strutz-Seebohm et al., 2005) and GluR1 (Strutz-Seebohm et al., 2005a). All of these transport proteins are also stimulated in the same cellular systems by SGK1, SGK3, and/or PKB; hence, the physiological relevance of these findings has to be considered with caution. To define more precisely the role of SGK2, it will be necessary to

[page 12]

carry out additional studies, using more relevant cell or animal systems and knocking down SGK2 by either RNA interference protocols or by gene inactivation. SGK3/CISK, which is better characterized than SGK2, was identified in a screen for antiapoptotic genes (Liu et al., 2000) and found to act downstream of the PI-3K pathway and in parallel with PKB/Akt. Moreover, it was demonstrated to phosphorylate and inhibit Bad (a proapoptotic protein) and FKHRL1, a proapoptotic transcription factor. Knockout (KO) mice have been generated; these mice are viable and fertile and have normal Na+ handling and glucose tolerance, as opposed to the KO mice of SGK1 or PKB/Akt2 (McCormick et al., 2004; Garofalo et al., 2003; Wulff et al., 2002; Cho et al., 2001). However, they display after birth a defect in hair follicle development, a defect preceded by disturbances in the β-catenein/Lef1 gene regulation (McCormick et al., 2004).

Anmerkungen

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(Hindemith), WiseWoman

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[Like SGK2, SGK3 has been implicated in the regulation of numerous] transporters and channels, including K+ channels (Gamper et al., (2002) Pflügers Arch; Henke et al., (2004) J cell Physiol); Embark et al., (2003) Pflügers Arch), Na+-K+-ATPase (Henke G. et al., (2002) Kidney Blood Press Res), the glutamate transporter EEAT1 (Boehmer et al., (2003) Cardiovasc Res), the cardiac voltage-gated Na+ channel SCN5A (Boehmer et al., (2003) J Neurochem), ENaC (Friedrich et al., (2003) Pflügers Arch), Na+-dicarboxylate cotransporter 1 (Böhmer et al., (2004) Biochem Biophys Res Commun), the chloride channel ClCa/barttin (Embark et al., (2004) Pflügers Arch), the epithelial Ca2+ channel TRPV5 (Embark et al., (2004) Pflügers Arch), the Na+-phosphate cotransporter NaPi2b (Palmada M. et al., (2004) Cell Physiol Biochem), the amino acid transporter ASCT2 (Palmada M. et al., (2005) Cell Physiol Biochem), GluR1, and GluR6 (Strutz-Seebohm et al., (2005); Strutz-Seebohm et al., (2005a) J Physiol). For the same reasons mentioned above for SGK2, additional studies on SGK3 will be necessary to evaluate the physiological relevance of these findings.

1.4. Tissue distribution of SGK isoforms

SGK isoforms are expressed in numerous tissues and cell lines. Among the three kinases, SGK1 (Waldegger et al., (1997) Proc Natl Acad Sci USA; Kobayashi et al., (1999) Biochem J) and SGK3 show the broadest distribution, with expression in many tissues including the brain, placenta, lung, liver, pancreas, kidney, heart and skeletal muscle. In situ hybridization studies localized SGK1 mRNA in several epithelial and/or nonepithelial cells within the brain (Wärntges et al., (2002) Cell Physiol Biochem; Nishida et al., (2004) Brain Res; Tsai et al., (2002) Proc Natl Acad Sci USA; Stichel et al., (2005) Eur J Neurosci; Gonzalez-Nicolini A. and McGinty F., (2002) Brain Res Gene ExpPatterns), eye (Rauz et al., (2003) Exp Eye Res; Rauz et al., (2003a) Invest Ophtalmol Vis Sci), lung (Wärntges et al., (2002) Cell Physiol Biochem) liver (Fillon et al., (2002) Comp Biochem Physiol A Mol Integr Physiol), ovary (Alliston et al., (2000) Endocrinology), pancreas (Klingel et al., (2000) Am J Physiol Gastrointest Liver Physiol), intestine (Waldegger et al., (1999) Gastroentherology) and kidney (Chen et al., (1999) Proc Natl Acad Sci USA; Friedrich et al., (2002) Kidney Blood Press res; Huber et al., (2001) Pflügers Archive).

SGK1 mRNA expression is established very early in embryonic development, as indicated by in situ hybridizations on whole-mount preparations of mouse embryo (Lee et al., (2001) Mech Dev). By embryonic day (E) 8.5, SGK1 is already highly expressed in the decidua and yolk sac. By days E9.5– E12.5 it is found in the developing heart, eye, and lung, and it becomes highly expressed by days E13.5–E16.5 in the brain choroid plexus, kidney distal tubules, bronchi/bronchiole, adrenal glands, liver, thymus, and intestine (Lee et al., (2001) Mech Dev). In contrast to SGK1 and SGK3, SGK2 reveals a more restricted distribution and is highly abundant only in the liver, kidney, and pancreas, where it is found in two different SGK2 species, referred to as SGK2α and SGK2β (Kobayashi et al., (1999) Biochem J). SGK isoform expression varies also between cell lines cultured in vitro. Similar to its expression pattern in vivo, SGK1 is broadly expressed in cultured cells and is readily detectable in, for example, hepatoma cells, fibroblasts and mammary tumor cells (Webster et al., (1993) J Biol Chem; Kobayashi et al., (1999) Biochem J). By contrast, SGK2 mRNA is expressed in hepatoma cells but not in fibroblasts, whereas SGK3 is found in fibroblasts but not in hepatoma cells. Remarkably, all three SGK isoforms are expressed in cells derived from the renal cortical collecting duct (Naray-Fejes-Toth et al., (2004) Proc Natl Acad Sci USA).

[p. 12]

Like SGK2, SGK3 has been implicated in the regulation of numerous transporters and channels, including K+ channels (Gamper et al., 2002; Henke et al., 2004; Embark et al., 2003), Na+,K+-ATPase (Henke et al., 2002), the glutamate transporter EEAT1 (Boehmer et al., 2003), the cardiac voltage-gated Na+ channel SCN5A (Boehmer et al., 2003), ENaC (Friedrich et al., 2003), Na+-dicarboxylate cotransporter 1 (Boehmer et al., 2004), the chloride channel ClCa/barttin (Embark et al., 2004), the epithelial Ca2+ channel TRPV5 (Embark et al., 2004), the Na+-phosphate cotransporter NaPi1b (Palmada et al., 2004), the amino acid transporter ASCT2 (Palmada et al., 2005), GluR1, and GluR6 (Strutz-Seebohm et al., 2005; Strutz-Seebohm et al., 2005a). For the same reasons mentioned above for SGK2, additional studies on SGK3 will be necessary to evaluate the physiological relevance of these findings. [...]

[p. 14]

1.4 Tissue Distribution of SGK Isoforms

SGK isoforms are expressed in numerous tissues and cell lines. Among the three kinases, SGK1 (Webster et al., 1993; Waldegger et al., 1997; Kobayashi et al., 1999) and Sgk3 (Kobayashi et al., 1999) show the broadest distribution, with expression in many tissues including the brain, placenta, lung, liver, pancreas, kidney, heart and skeletal muscle. In situ hybridization studies localized SGK1 mRNA in several epithelial and/or nonepithelial cells within the brain (Warntges et al., 2002; Nishida et al., 2004; Tsai et al., 2002; Stichel et al., 2005; Gonzalez-Nicolini and McGinty 2003), eye (Rauz et al., 2003; Rauz et al., 2003a), lung (Waerntges et al., 2002), liver (Fillon et al., 2002), ovary (Alliston et al., 2000), pancreas (Klingel et al., 2000), intestine (Waldegger et al., 1999), and kidney (Chen et al., 1999; Friedrich et al., 2002; Huber et al., 2001). SGK1 mRNA expression is established very early in embryonic development, as indicated by in situ hybridizations on whole-mount preparations of mouse embryo (Lee et al., 2001). By embryonic day (E) 8.5, SGK1 is already highly expressed in the decidua and yolk sac. By days E9.5– E12.5 it is found in the developing heart, eye, and lung, and it becomes highly expressed by days E13.5–E16.5 in the brain choroid plexus, kidney distal tubules, bronchi/brochioli, adrenal glands, liver, thymus, and intestine (Lee et al., 2001). In contrast to SGK1 and SGK3, SGK2 reveals a more restricted distribution and is highly abundant only in the liver, kidney, and pancreas, where it is found in two different SGK2 species, referred to as SGK2α and

[p. 15]

SGK2β (Kobayashi et al., 1999). SGK isoform expression varies also between cell lines cultured in vitro. Similar to its expression pattern in vivo, SGK1 is broadly expressed in cultured cells and is readily detectable in, for example, hepatoma cells, fibroblasts, and mammary tumor cells (Webster et al., 1993; Kobayashi et al., 1999). By contrast, SGK2 mRNA is expressed in hepatoma cells but not in fibroblasts, whereas SGK3 is found in fibroblasts but not in hepatoma cells. Remarkably, all three SGK isoforms are expressed in cells derived from the renal cortical collecting duct (Naray-Fejes-Toth et al., 2004).

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a) Role of SGK1 in aldosterone dependent Na+ reabsorption

Although SGK isoforms are expressed in various tissues and cell types, the role of SGK1 in aldosterone-dependent regulation of Na+ homeostasis is the best-studied function of these kinases with respect to epithelial ion transport. The kidneys play a pivotal role in the maintenance of Na+ homeostasis. Urinary Na+ excretion must be tightly regulated to maintain a constant extracellular volume during varying dietary Na+ intake and extrarenal Na+ losses. The final control of renal Na+ excretion is achieved by the ASDN i.e. the late distal convoluted tubule, the connecting tubule and the cortical as well as the medullary collecting ducts (CCD and MCD respectively) (Loffing J. et al., (2001) Am J Physiol Renal Physiol).

1.5 Role of SGK1 in Aldosterone Dependent Na+ Reabsorption

Although SGK isoforms are expressed in various tissues and cell types, the role of SGK1 in aldosterone-dependent regulation of Na+ homeostasis is the best-studied function of these kinases with respect to epithelial ion transport. The kidneys play a pivotal role in the maintenance of Na+ homeostasis. Urinary Na+ excretion must be tightly regulated to maintain a constant extracellular volume during varying dietary Na+ intake and extrarenal Na+ losses. The final control of renal Na+ excretion is achieved by the ASDN i.e. the late distal convoluted tubule, the connecting tubule, and the cortical as well as the medullary collecting ducts (CCD and MCD respectively) (Loffing et al., 2001).

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Transepithelial Na+ transport in these segments is accomplished by Na+ entry into the epithelial cells via the epithelial Na+ channel (ENaC) in the luminal membrane and by exit of Na+ through the Na+, K+-ATPase in the basolateral plasma membrane. ENaC represents the rate limiting step in this process and is highly regulated (Kellenberger S. and Schild L., (2002) J Physiol). It is composed of three subunits (α, β and γ) (Canessa CM. et al., (1994) Nature; Lingueglia et al., (1993) FEBS Lett; Lingueglia et al., (1994) J Biol Chem) with a stoichiometry of 2α1β1γ (Firsov et al., (1998) EMBO J), although other stoichiometries have also been proposed (octa- or nonamers) (Eskandari et al., (1999) J Biol Chem; Snyder et al., (1998) J Biol Chem). Its subunits have a similar topology, with two transmembrane domains, one extracellular loop, and two cytoplasmic ends (Renard et al., (1994) J Biol Chem; Canessa CM. et al., (1994) Nature; Snyder et al., (1994) PMID). Each subunit also contains, at its C-terminal end, a PY-motif (P-P-X-Y, where P is a proline, Y a tyrosine, and X any amino acid), which is known as protein: protein interaction motifs that can interact with tryptophan (W)-rich WW domains (Chen HI. and Sudol M., (1995) Proc Natl Acad Sci USA; Staub O. and Rotin D., (1996) Am Physiol Soc).

The importance of these PY-motifs for ENaC regulation has been recognized by the findings that most cases of Liddle’s syndrome, K+-ATPase (Zecevic M. et al., (2004) Pflügers Arch; Setiawan I. et al., (2002) Pflügers Arch) with SGK1 profoundly increases the activity of both Na+- transporting proteins. Likewise, SGK2 and SGK3 stimulate ENaC (Friedrich B. et al., (2003) Pflügers Arch) and Na+- K+-ATPase (Henke G. et al., (2002) Kidney Blood Press Res).

Transepithelial Na+ transport in these segments is accomplished by Na+ entry into the epithelial cells via the epithelial Na+ channel (ENaC) in the luminal membrane and by exit of Na+ through the Na+, K+-ATPase in the basolateral plasma membrane. ENaC represents the rate limiting step in this process and is highly regulated (Kellenberger and Schild 2002). It is composed of three subunits (α, β and γ) (Canessa et al., 1994; Canessa et al., 1994; Lingueglia et al., 1993; Lingueglia et al., 1994) with a stoichiometry of 2α1β1γ (Firsov et al., 1998), although other stoichiometries have also been proposed (octa- or nonamers) (Eskandari et al., 1999; Snyder et al., 1998). Its subunits have a similar topology, with two transmembrane domains, one extracellular loop, and two cytoplasmic ends (Renard et al., 1994; Canessa et al., 1994; Snyder et al., 1994). Each subunit also contains, at its C-terminal end, a PY-motif (P-P-X-Y, where P is a proline, Y a tyrosine, and X any amino acid), which is known as protein:protein interaction motifs that can interact with tryptophan (W)-rich WW domains (Chen and Sudol 1995; Staub and Rotin 1996). The importance of these PY-motifs for ENaC regulation has been recognized by the findings that most cases of Liddle’s syndrome [(Liddle et al., 1963)]

[p. 16]


[...], K+-ATPase (Zecevic et al., 2004; Setiawan et al., 2002) with SGK1 profoundly increases the activity of both Na+-transporting proteins. Likewise, SGK2 and SGK3 stimulate ENaC (Friedrich et al., 2003) and Na+,K+-ATPase (Henke et al., 2002).

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Note that the first sentence of the second paragraph makes little sense, as it is a combination of two unrelated half-sentences of the source, the first one ending just at the page break from page 15 to page 16.

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The stimulatory effect of SGK1 on ENaC is related both to an increased number of channels in the plasma membrane (Lang F. et al., (2000) Proc Natl Acad Sci USA; Loffing J. et al., (2001) Am J Physiol Renal Physiol; Alvarez de la Rosa D. et al., (1999) J Biol Chem) and an activation of channels already present in the membrane (Diakov A. and Korbmacher C., (2004) J Biol Chem). The first effect likely involves the action of Nedd4-2, as there are several consensus phosphorylation motifs (2–3 depending on the splice variant) on Nedd4-2 and a PY-motif on SGK1 that may serve as a binding site for Nedd4-2.

In Xenopus oocytes, SGK1 induces Nedd4-2 phosphorylation on two of these phosphorylation sites (primarily Ser444, but also Ser338) (Embark HM. et al., (2004) Cell Physiol Biochem; Palmada M. et al., (2004) Am J Physiol Gastrointest Liver Physiol; Debonneville C. et al., (2001) EMBO J), which decreases the interaction of Nedd4-2 with ENaC and finally leads to an enhanced expression and activity of ENaC at the cell surface (Debonneville C. et al., (2001) EMBO J).

The stimulatory effect of SGK1 on ENaC is related both to an increased number of channels in the plasma membrane (Lang et al., 2000; Loffing et al., 2001; Alvarez de la Rosa et al., 1999) and an activation of channels already present in the membrane (Diakov and Korbmacher 2004). The first effect likely involves the action of Nedd4-2, as there are several consensus phosphorylation motifs (2–3 depending on the splice variant) on Nedd4-2 and a PY-motif on SGK1 that may serve as a binding site for Nedd4-2. In Xenopus oocytes, SGK1 induces Nedd4-2 phosphorylation on two of these phosphorylation sites (primarily Ser444, but also Ser338) (Embark et al., 2004; Palmada et al., 2004; Debonneville et al., 2001), which decreases the interaction of Nedd4-2 with ENaC and finally leads to an enhanced expression and activity of ENaC at the cell surface (Debonneville et al., 2001).
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This inhibitory effect of SGK1 on Nedd4-2 likely involves 14-3-3 proteins as phosphorylation of Ser444 in Nedd4-2 creates a possible binding site for such proteins, an inherited form of salt-sensitive hypertension are caused by mutations in the genes encoding β- and γ -ENaC (Hansson JH. et al., (1995) Proc Natl Acad Sci USA; Shimkets RA. et al., (1994) Cell). These mutations invariably cause either the deletion or the mutation of the PY-motifs on these subunits. When such Liddle channels are expressed in heterologous systems, increases in both the density at the cell surface and the open probability of ENaC are observed (Firsov et al., (1996) Proc Natl Acad Sci USA; Snyder PM. et al., (1994) Cell; Schild et al., (1995) Proc Natl Acad Sci USA; Schild et al., (1996) EMBO J). Loffing and his coworkers, has demonstrated that these PY-motifs are the binding sites for ubiquitin-protein ligases of the Nedd4/Nedd4-like family (Kamynina E. et al., (2001) EMBO J) and particularly of Nedd4-2 (Kamynina E. et al., (2001) EMBO J; Snyder PM. et al., (2004) J Biol Chem).

It is thought that Nedd4-2 binds via its WW domains with the PY-motifs of ENaC and ubiquitylates ENaC on its own α and γ subunits, consequently leading to the internalization and degradation of ENaC in the endosomal/lysosomal system (Snyder PM. et al., (2004) J Biol Chem). In Liddle’s syndrome, this mechanism is impaired owing to the inactivation of a PY-motif, causing the accumulation of ENaC at the plasma membrane (Kamynina E. and Staub O., (2002) Am J Physiol Renal Physiol). The activity of ENaC and the Na+, K+-ATPase is tightly regulated by aldosterone and by SGK1 (Vallon V. et al., (2005) Am J Physiol Regul Integr Comp Physiol; Bhargava A. et al., (2004) Trends Endocrinol Metab).

[...], an inherited form of salt-sensitive hypertension are caused by mutations in the genes encoding β- and γ -ENaC (Hansson et al., 1995; Shimkets et al., 1994). These mutations invariably cause either the deletion or the mutation of the PY-motifs on these subunits. When such Liddle channels are expressed in heterologous systems, increases in both the density at the cell surface and the open probability of ENaC are observed (Firsov et al., 1996; Snyder et al., 1995; Schild et al., 1995; Schild et al., 1996). Loffing and his coworkers, has demonstrated that these PY-motifs are the binding sites for ubiquitin-protein ligases of the Nedd4/Nedd4-like family (Kamynina et al., 2001; Kamynina et al., 2001a ) and particularly of Nedd4-2 (Kamynina et al., 2001; Kamynina et al., 2001a; Snyder et al., 2004). It is thought that Nedd4-2 binds via its WW domains with the PY-motifs of ENaC and ubiquitylates ENaC on its α and γ subunits, consequently leading to the internalization and degradation of ENaC in the endosomal/lysosomal system (Snyder et al., 2004). In Liddle’s syndrome, this mechanism is impaired owing to the inactivation of a PY-motif, causing the accumulation of ENaC at the plasma membrane (Kamynina and Staub 2002). The activity of ENaC and the Na+, K+-ATPase is tightly regulated by aldosterone and by SGK1 (Kellenberger and Schild 2002; Vallon et al., 2005; Bhargava et al., 2004). [...] This inhibitory effect of SGK1 on Nedd4-2 likely involves 14-3-3 proteins as phosphorylation of Ser444 in Nedd4-2 creates a possible binding site for such proteins
Anmerkungen

The source is not given.

Note that the first sentence makes little sense, as it is a combination of two unrelated half-sentences of the source. Apparently the last line of the source on page 16 has not been continued with the first line on page 17, but with the first line on page 16 again, leading to this result. Also, the source writes Ser444, Dsa writes Ser444 constistently.

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(Hindemith), WiseWoman

[8.] Dsa/Fragment 035 01 - Diskussion
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Experiments in heterologous expression systems (i.e., X. laevis oocytes) revealed that coexpression of either ENaC or Na+ (consensus: R-S-X-pS-X-P) increases SGK stimulation. Indeed, in X. laevis oocytes, SGK1 increases the binding of 14-3-3 to Nedd4-2 in a phosphorylation-dependent manner, a dominant-negative 14-3-3 mutant profoundly attenuates SGK1-dependent stimulation of ENaC, and overexpression of the 14-3-3 protein impairs Nedd4-2-dependent ubiquitylation of ENaC (Ichimura T. et al., (2005) J Biol Chem).

In addition to this indirect action of SGK1 on ENaC cell surface abundance, it was proposed that SGK1 can directly interact with ENaC (Wang J. et al., (2001) Am J Physiol Renal Physiol) and increase ENaC channel activity by phosphorylating the α-ENaC subunits (Diakov A. and Korbmacher C., (2004) J Biol Chem). Diakov and Korbmacher used outsideout membrane patches of X. laevis oocytes expressing rat ENaC to demonstrate that addition of recombinant, constitutively active SGK1 directly stimulates ENaC currents two- to threefold. An alanine mutation of the serine residue in the SGK1 consensus R-X-R-X-X-S phosphorylation motif abolishes the stimulatory effect on ENaC in this experimental setting.

Experiments in native Xenopus A6 cells expressing endogenous SGK1 and ENaC further confirmed that the action of SGK1 on ENaC is complex and likely involves (a) increases in the subunit abundance in the plasma membrane and (b) activation of channels already in the plasma membrane combined with an increase in ENaC open probability (Alvarez de la Rosa D. et al., (2004) J Physiol). However, in this model the stimulatory effect on ENaC channel activity cannot be explained by a direct SGK1-dependent phosphorylation of α-ENaC because Xenopus α-ENaC does not contain the SGK1 consensus phosphorylation motif. That direct phosphorylation of ENaC at the SGK1 consensus site is not essential for ENaC activation is also supported by data from Lang and coworkers (Lang F. et al., (2000) Proc Natl Acad Sci USA; Friedrich B. et al., (2002) Kidney Blood Press Res) that showed that channels with a serine-to-alanine mutation within the consensus site of α-ENaC are still rigorously upregulated by coexpression of SGK1 in Xenopus oocytes.

NDRG-2, which is an aldosterone-induced protein in the ASDN, is another target of SGK1 (Boulkroum S. et al., (2002) J Biol Chem; Murray JT. et al., (2004) Biochem J). Although the functional role of NDRG-2 in the ASDN is not known, this protein may also have some function in the SGK1-dependent signaling cascade related to Na+ transport. As an aldosterone-induced protein, SGK1 is thought to mediate at least some of the physiological effects of aldosterone on ENaC and Na+, K+-ATPase. The stimulatory effect of aldosterone (or of dexamethasone) on SGK1 expression has now been firmly documented in several studies on various in vitro and in vivo systems, including Xenopus A6 cells (Bhargava A. et al., (2004) Trends Endocrinol Metab), primary rabbit CCD cells (Narey-Fejes-Toth et al., (1999) J BiolChem), mouse inner MCD cells (Gumz et al., (2003) Am J Physiol Renal Physiol), mouse mpkCCDcl4 (Flores SY. et al., (2005) J Am Soc Nephrol), mouse M1 cells (Helms MN. et al., (2003) Am J Physiol Renal Phyisol) and mouse and rat kidneys (Chen et al., (1999) Proc Natl Acad Sci USA; Loffing et al.,(2001) Am J Physiol Renal Physiol; Bhargava A. et al., (2001) Endocrinology). Corticosteroids rapidly (within 30 minutes) induce SGK1 at the mRNA and/or protein levels. This induction precedes or at least coincides with enhanced phosphorylation of Nedd4-2 (Flores SY. et al., (2005) J Am Soc Nephrol), the activation of transepithelial Na+ transport in cultured renal epithelia (Naray-Fejes-Toth A. et al., (1999) J Biol Chem; Bhargava A. et al., (2004) Trends Endocrinol Metab; Flores SY. et al., (2005) J Am Soc Nephrol), and reduced renal Na+ secretion in intact animals (Bhargava A. et al., (2001) Endocrinology).

Experiments in heterologous expression systems (i.e., X. laevis oocytes) revealed that coexpression of either ENaC or Na+, [...]

[page 17]

(consensus: R-S-X-pS-X-P). Indeed, in X. laevis oocytes, SGK1 increases the binding of 14-3-3 to Nedd4-2 in a phosphorylation-dependent manner, a dominant-negative 14-3-3 mutant profoundly attenuates SGK1-dependent stimulation of ENaC, and overexpression of the 14-3-3 protein impairs Nedd4-2-dependent ubiquitylation of ENaC (Ichimura et al., 2005).

In addition to this indirect action of SGK1 on ENaC cell surface abundance, it was proposed that SGK1 can directly interact with ENaC (Wang et al., 2001) and increase ENaC channel activity by phosphorylating the α-ENaC subunits (Diakov and Korbmacher 2004). Diakov & Korbmacher (2004) used outside-out membrane patches of X. laevis oocytes expressing rat ENaC to demonstrate that addition of recombinant, constitutively active SGK1 directly stimulates ENaC currents two- to threefold. An alanine mutation of the serine residue in the SGK1 consensus R-X-R-X-X-S phosphorylation motif abolishes the stimulatory effect on ENaC in this experimental setting. Experiments in native Xenopus A6 cells expressing endogenous SGK1 and ENaC further confirmed that the action of SGK1 on ENaC is complex and likely involves (a) increases in the subunit abundance in the plasma membrane and (b) activation of channels already in the plasma membrane combined with an increase in ENaC open probability (Alvarez de la Rosa et al., 2004). However, in this model the stimulatory effect on ENaC channel activity cannot be explained by a direct SGK1-dependent phosphorylation of α-ENaC because Xenopus α-ENaC does not contain the SGK1 consensus phosphorylation motif. That direct phosphorylation of ENaC at the SGK1 consensus site is not essential for ENaC activation is also supported by data from Lang and coworkers (Lang et al., 2000; Friedrich et al., 2002) that showed that channels with a serine-to-alanine mutation within the consensus site of α-ENaC are still rigorously upregulated by coexpression of SGK1 in Xenopus oocytes. NDRG-2, which is an aldosterone-induced protein in the ASDN, is another target of SGK1 (Boulkroum et al., 2002; Murray et al., 2004). Although the functional role of NDRG-2 in the ASDN is not known, this protein may also have some function in the SGK1-dependent signaling cascade related to Na+ transport. As an aldosterone-induced protein, SGK1 is thought to mediate at least some of the physiological effects of aldosterone on ENaC and Na+,K+-ATPase. The stimulatory effect of aldosterone (or of dexamethasone) on SGK1 expression has now been firmly documented in several studies on various in vitro and in vivo systems, including Xenopus A6 cells (Bhargava et al., 20004), primary rabbit CCD cells (Narey-Fejes-Toth et

[page 18]

al., 1999), mouse inner MCD cells (Gumz et al., 2003), mouse mpkCCDcl4 (Flores et al., 2005), mouse M1 cells (Helms et al., 2003 ), and mouse and rat kidneys (Chen et al., 1999; Loffing et al., 2001; Bhargava et al., 2001). Corticosteroids rapidly (within 30 minutes) induce SGK1 at the mRNA and/or protein levels. This induction precedes or at least coincides with enhanced phosphorylation of Nedd4-2 (Flores et al., 2005), the activation of transepithelial Na+ transport in cultured renal epithelia (Naray-Fejes-Toth et al., 1999; Bhargava et al., 2004; Flores et al., 2005), and reduced renal Na+ secretion in intact animals (Bhargava et al., 2001).

Anmerkungen

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(Hindemith), WiseWoman

[9.] Dsa/Fragment 036 01 - Diskussion
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At least part of the stimulatory effect of aldosterone on SGK1 appears to be mediated by activation of the MR, as indicated by findings in primary rabbit collecting duct cells in vitro (Narey-Fejes-Toth et al., (1999) [sic] J Biol Chem) and kidneys in vivo (Bhargava A. et al., (2001) Endocrinology). Consistently, physiologically relevant concentrations of aldosterone are sufficient to significantly induce SGK1 mRNA in the renal cortex and outer medulla (Muller OG. et al., (2003) J Am Soc Nephrol). The physiological importance of aldosterone in SGK induction is also supported by the fact that dietary Na+ restriction, which physiologically increases plasma aldosterone, induces SGK1 mRNA in the renal cortex (Farjah M. et al., (2003) Hypertension). The aldosterone-dependent induction of SGK1 occurs specifically in the ENaC-positive cells of the ASDN, whereas SGK1 expression in other nephron portions such as the thick ascending limb or the proximal tubule is not increased by aldosterone. Likewise, the high level of expression of SGK1 in the renal papilla is not further stimulated by aldosterone, suggesting that SGK1 expression at this site is controlled by factors other than aldosterone. The renal papilla plays an important role for the urinary concentration mechanism, and the cells in the renal papilla can be exposed to a large variation in extracellular osmolarity depending on the requirements for diuresis to antidiuresis. SGK1 expression is strongly modulated by osmotic cell shrinkage and swelling (Waldegger S. et al., (1997) Proc Natl Acad Sci USA; Rozansky DJ. et al., (2002) Am J Renal Physiol), and it is therefore conceivable that SGK1 participates in the functional adaptation of the renal papilla cells to fluctuation of extracellular osmolarity.

Consistent with this notion, recent data suggest that SGK1 mediates the osmotic induction of the type A natriuretic peptide receptor (NPR-A) in rat inner MCD cells (Chen S. et al., (2004) Hypertension). Aldosterone also controls SGK1 expression in the distal colon (Coric CM. et al., (2004) Am J Physiol Gastrointest Liver Physiol; Bhargava A. et al., (2001) Endocrinology). Aldosterone-dependent Na+ reabsorption at this site may help to limit extrarenal Na+ losses during conditions of dietary Na+ restriction. Transepithelial Na+ transport is achieved mainly by epithelial cells that are situated at the tips of colonic crypts and that express high levels of ENaC (Coric CM. et al., (2004) Am J Physiol Gastrointest Liver Physiol) and SGK1 (Waldegger S. et al., (1999) Gastroenterology; Coric CM. et al., (2004) Am J Physiol Gastrointest Liver Physiol). In spite of these data pointing to aldosterone-dependent regulation of ENaC via SGK1, recent Western blot and immunohistochemical studies on rat kidney and colon, which reported no or rather modest aldosterone-dependent induction of SGK1 at the protein level, were interpreted to question the significance of aldosterone-dependent induction of SGK1 for ENaC-mediated Na+ transport regulation (Coric CM. et al., (2004) Am J Physiol Gastrointest Liver Physiol). Support for a functional significance of SGK1 in regulation of transepithelial Na+ transport comes from experiments in X. laevis A6 cells and in mouse M1 CCD cells.

Transfection of A6 or M1 cells with SGK1 leads to an increase in transepithelial Na+ transport, whereas transfection of a dominant-negative “kinase-dead” SGK1 mutant or an antisense SGK1 transcript abolishes dexamethasone- and/or insulin-dependent regulation of transepithelial Na+ transport (Alvarez de Rosa D. et al., (2003) J Physiol; Faletti CJ. et al., (2002) Am J Physiol Cell Physiol). Likewise, the use of interfering RNA to knockdown SGK1 expression in A6 cells results in a significant reduction in SGK1 protein levels and a ~50% reduction in dexamethasone-induced short-circuit currents (Bhargava A. et al., (2001) Endocrinology). Consistent with these in vitro findings, experiments in SGK1 KO (sgk1−/−) mice supported the importance of SGK1 for aldosterone-dependent regulation of renal Na+ transport (Wulff et al., (2002) J Clin Invest).

At least part of the stimulatory effect of aldosterone on SGK1 appears to be mediated by activation of the MR, as indicated by findings in primary rabbit collecting duct cells in vitro (Naray-Fejes-Toth et al., 1999) and kidneys in vivo (Bhargava et al., 2001). Consistently, physiologically relevant concentrations of aldosterone are sufficient to significantly induce SGK1 mRNA in the renal cortex and outer medulla (Muller et al., 2003). The physiological importance of aldosterone in SGK induction is also supported by the fact that dietary Na+ restriction, which physiologically increases plasma aldosterone, induces SGK1 mRNA in the renal cortex (Farjah et al., 2003). The aldosterone-dependent induction of SGK1 occurs specifically in the ENaC-positive cells of the ASDN, whereas SGK1 expression in other nephron portions such as the thick ascending limb or the proximal tubule is not increased by aldosterone. Likewise, the high level of expression of SGK1 in the renal papilla is not further stimulated by aldosterone, suggesting that SGK1 expression at this site is controlled by factors other than aldosterone. The renal papilla plays an important role for the urinary concentration mechanism, and the cells in the renal papilla can be exposed to a large variation in extracellular osmolarity depending on the requirements for diuresis to antidiuresis. SGK1 expression is strongly modulated by osmotic cell shrinkage and swelling (Waldegger et al., 1997; Rozansky et al., 2002), and it is therefore conceivable that SGK1 participates in the functional adaptation of the renal papilla cells to fluctuation of extracellular osmolarity. Consistent with this notion, recent data suggest that SGK1 mediates the osmotic induction of the type A natriuretic peptide receptor (NPR-A) in rat inner MCD cells (Chen et al., 2004). Aldosterone also controls SGK1 expression in the distal colon (Coric et al., 2004; Bhargava et al., 2001). Aldosterone-dependent Na+ reabsorption at this site may help to limit extrarenal Na+ losses during conditions of dietary Na+ restriction. Transepithelial Na+ transport is achieved mainly by epithelial cells that are situated at the tips of colonic crypts and that express high levels of

[page 19]

ENaC (Coric et al., 2004) and Sgk1 (Waldegger et al., 1999; Coric et al., 2004). In spite of these data pointing to aldosterone-dependent regulation of ENaC via SGK1, recent Western blot and immunohistochemical studies on rat kidney and colon, which reported no or rather modest aldosterone-dependent induction of SGK1 at the protein level, were interpreted to question the significance of aldosterone-dependent induction of SGK1 for ENaC-mediated Na+ transport regulation (Coric et al., 2004). Support for a functional significance of SGK1 in regulation of transepithelial Na+ transport comes from experiments in X. laevis A6 cells and in mouse M1 CCD cells. Transfection of A6 or M1 cells with SGK1 leads to an increase in transepithelial Na+ transport, whereas transfection of a dominant-negative “kinase-dead” SGK1 mutant or an antisense SGK1 transcript abolishes dexamethasone- and/or insulin-dependent regulation of transepithelial Na+ transport (Alvarez de Rosa et al., 2003; Faletti et al., 2002). Likewise, the use of interfering RNA to knockdown SGK1 expression in A6 cells results in a significant reduction in SGK1 protein levels and a ~50% reduction in dexamethasone-induced short-circuit currents (Bhargava et al., 2004). Consistent with these in vitro findings, experiments in SGK1 KO (sgk1-/-) mice supported the importance of SGK1 for aldosterone-dependent regulation of renal Na+ transport (Wulff et al., 2002).

Anmerkungen

The source is not given.

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(Hindemith), WiseWoman

[10.] Dsa/Fragment 037 01 - Diskussion
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[Under a standard diet, the KO mice have] unaltered Na+ excretion as compared to their wildtype littermates. However, plasma aldosterone levels are significantly increased in sgk1−/− mice, suggesting extracellular volume contraction.

Under dietary Na+ restriction, activated compensatory mechanisms are no longer sufficient to keep the mice in Na+ balance, and mice disclosed significant loss in renal NaCl and in body weight. Experiments on collecting ducts perfused ex vivo revealed significantly lower transepithelial amiloride-sensitive potential differences, consistent with a reduced Na transport activity in the CCD. Although apical localization of ENaC was seen in both Na+- restricted sgk1+/+ and sgk1−/− mice, the apical localization of ENaC is inappropriately low in the sgk1−/− mice given the several fold higher plasma aldosterone levels in the KO mice.

Nevertheless, these data, together with the rather mild phenotype of sgk1−/− mice, as compared to the much more severe and life-threatening phenotypes of MR or ENaC ko mice, suggest that (a) aldosterone-dependent control of ENaC function does not solely rely on the induction and activation of SGK1 and (b) some redundancy exists in the signal transduction pathway that controls ENaC activity. Consistent with these ideas, Loffing and his coworkers found significant phosphorylation of the SGK1 target Nedd4-2 in mouse mpkCCDcl4 cells in vitro and in rat collecting ducts in vivo in the absence of any aldosterone and detectable SGK1 protein expression (Flores SY. et al., (2005) J Am Soc Nephrol). In addition to aldosterone-dependent regulation of renal Nareabsorption [sic] , SGK1 appears to be involved also in the regulation of aldosterone-induced salt appetite. Sgk1+/+ and sgk1−/− mice show a similar salt intake under standard conditions. Treatment with the synthetic aldosterone analogue deoxycorticosterone-acetate (DOCA) increases Na+ intake much more in sgk1+/+ mice than in sgk1−/− mice. The underlying mechanism for the reduced mineralocorticoid-induced salt intake is unclear (Vallon V. et al., (2005) Am J Physiol Regul Integr Comp Physiol).

b) Role of SGK1 in renal K+ secretion

Aside from its stimulatory effect on renal Na+ reabsorption, aldosterone has strong kaliuretic action. Renal K+ secretion also takes place in the ASDN and is likely mediated by the renal outer medullary K+ channel ROMK. ROMK is coexpressed with ENaC in the ASDN cells, and Na+ reabsorption via ENaC provides the necessary driving force for K+ secretion. Consistently, pharmacological inhibition (i.e., by amiloride) or genetic loss of function (i.e., pseudohypoaldosteronism (PHA) type 1) of ENaC lower renal K+ secretion and predispose one to hyperkalemia.

It remains unresolved whether the kaliuretic effect of aldosterone is entirely secondary to the activation of ENaC-mediated Na+ reabsorption or whether aldosterone directly regulates ROMK function.

Under a standard diet, the KO mice have unaltered Na+ excretion as compared to their wildtype littermates. However, plasma aldosterone levels are significantly increased in sgk1-/- mice, suggesting extracellular volume contraction. Under dietary Na+ restriction, activated compensatory mechanisms are no longer sufficient to keep the mice in Na+ balance, and mice disclosed significant loss in renal NaCl and in body weight. Experiments on collecting ducts perfused ex vivo revealed significantly lower transepithelial amiloride-sensitive potential differences, consistent with a reduced Na+ transport activity in the CCD. Although apical localization of ENaC was seen in both Na+-restricted sgk+/+ [sic] and sgk1-/- mice, the apical localization of ENaC is inappropriately low in the sgk1-/- mice given the severalfold higher plasma aldosterone levels in the KO mice. Nevertheless, these data, together with the rather mild phenotype of sgk1-/- mice, as compared to the much more severe and life-threatening phenotypes of MR or ENaC KO mice, suggest that (a) aldosterone-dependent control of ENaC function does not solely rely on the induction and activation of SGK1 and (b) some redundancy exists in the signal transduction pathway that controls ENaC activity. Consistent with these ideas, Loffing and his coworkers found significant phosphorylation of the SGK1 target Nedd4-2 in mouse mpkCCDcl4 cells in vitro

[page 20]

and in rat collecting ducts in vivo in the absence of any aldosterone and detectable SGK1 protein expression (Flores et al., 2005). In addition to aldosterone-dependent regulation of renal Na+ reabsorption, SGK1 appears to be involved also in the regulation of aldosterone-induced salt appetite. Sgk1+/+ and sgk1-/- mice show a similar salt intake under standard conditions. Treatment with the synthetic aldosterone analogue deoxycorticosterone-acetate (DOCA) increases Na+ intake much more in Sgk1+/+ mice than in sgk1-/- mice. The underlying mechanism for the reduced mineralocorticoid-induced salt intake is unclear (Vallon et al., 2005).

1.6 Role of SGK1 in Renal K+ Secretion

Aside from its stimulatory effect on renal Na+ reabsorption, aldosterone has strong kaliuretic action. Renal K+ secretion also takes place in the ASDN and is likely mediated by the renal outer medullary K+ channel ROMK. ROMK is coexpressed with ENaC in the ASDN cells, and Na+ reabsorption via ENaC provides the necessary driving force for K+ secretion. Consistently, pharmacological inhibition (i.e., by amiloride) or genetic loss of function [i.e., pseudohypoaldosteronism (PHA) type 1] of ENaC lower renal K+ secretion and predispose one to hyperkalemia. It remains unresolved whether the kaliuretic effect of aldosterone is entirely secondary to the activation of ENaC-mediated Na+ reabsorption or whether aldosterone directly regulates ROMK function.

Anmerkungen

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(Hindemith), WiseWoman

[11.] Dsa/Fragment 038 01 - Diskussion
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Patch-clamp studies on rat CCDs found no measurable effect of acute aldosterone administration on K+ channel number, open probability, or conductance (Palmer LG. et al., (1994) Am J Physiol). However, some data suggested that aldosterone induces renal K+ secretion already at aldosterone concentrations that do not exhibit any measurable effect on urinary Na+ excretion (Bhargava et al., (2001) Endocrinology). Moreover, high K+ intake increases ROMK activity more efficiently in intact rats than in adrenalectomized animals, suggesting that aldosterone may have at least a permissive effect on ROMK activation (Palmer LG. et al., (1994) Am J Physiol).

Consistent with a possible role of aldosterone in ROMK regulation, recent studies in heterologous expression systems advocated a regulatory action of aldosterone-induced SGK1 on ROMK cell surface activity and abundance (Palmada M. et al., (2003) Biochem Biophys Res Commun). The regulatory role of SGK1 with regard to ROMK may be indirect via increased interaction with the Na+, H+ exchanger–regulating factor 2 (NHERF2) (Palmada M. et al., (2003) Biochem Biophys Res Commun) or direct via increased phosphorylation of ROMK at a serine residue within the canonical SGK1 consensus phosphorylation motif (Yoo D. et al., (2003) J Biol Chem).

Patch-clamp studies on rat CCDs found no measurable effect of acute aldosterone administration on K+ channel number, open probability, or conductance (Palmer et al., 1994). However, some data suggested that aldosterone induces renal K+ secretion already at aldosterone concentrations that do not exhibit any measurable effect on urinary Na+ excretion (Bhargava et al., 2001). Moreover, high K+ intake increases ROMK activity more efficiently in intact rats than in adrenalectomized animals, suggesting that aldosterone may have at least a permissive effect on ROMK activation (Palmer et al., 1994). Consistent with a possible role of aldosterone in ROMK regulation, recent studies in heterologous expression systems advocated a regulatory action of aldosterone-induced SGK1 on ROMK cell surface activity and abundance (Palmada et al., 2003, Palmada et al., 2003a). The regulatory role of SGK1 with regard to ROMK may be indirect via increased interaction with the Na+, H+ exchanger–regulating factor 2 (NHERF2) (Palmada et al., 2003, Palmada et al., 2003a) or direct via

[page 21]

increased phosphorylation of ROMK at a serine residue within the canonical SGK1 consensus phosphorylation motif (Yoo et al., 2003).

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The in vivo significance of SGK1 in regulation of renal K+ transport was recently analyzed in SGK1 KO mice. These mice indeed show a disturbed adaptation to an acute and chronic K+ load, but, as indicated by electrophysiological and immunohistochemical data obtained from these mice after a chronic potassium load, this maladaptation likely is related to altered ENaC (or Na+, K+-ATPase) activity in the ASDN cells rather than to inhibition of ROMK cell surface targeting or activity (Huang DY. et al., (2004) J Am Soc Neprhol). The in vivo significance of SGK1 in regulation of renal K+ transport was recently analyzed in SGK1 KO mice. These mice indeed show a disturbed adaptation to an acute and chronic K+ load, but, as indicated by electrophysiological and immunohistochemical data obtained from these mice after a chronic potassium load, this maladaptation likely is related to altered ENaC (or Na+,K+-ATPase) activity in the ASDN cells rather than to inhibition of ROMK cell surface targeting or activity (Huang et al., 2004).
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Seite(n): 34, Zeilen: 4ff
Mice deficient in SGK1 (sgk1–/–) were generated and bred as previously described (Huang et al., (2004) J Am Soc Nephol; Wulff et al., (2002) J Clin Invest; Huang et al., (2004) J Am Soc Nephol). In brief, a conditional targeting vector was generated from a 7-kb fragment encompassing the entire transcribed region on 12 exons. The neomycin resistance cassette was flanked by two loxP sites and inserted into intron 11. Exons 4–11, which code for the sgk1 kinase domain, were “floxed” by inserting a third loxP site into intron 3. A clone with a recombination between the first and third loxP site (type I recombination) was injected into C57BL/6 blastocytes. Male chimeras were bred to C57BL/6 and 129/SvJ females. Heterozygous SGK1-deficient mice were backcrossed to 129/SvJ wild-type mice (Charles River, Sulzfeld, Germany) for ten generations and then intercrossed to generate homozygous SGK1 knockout mice (sgk1−/−) and their wild type littermates (sgk1+/+). Mice deficient in SGK1 (sgk1-/-) were generated and bred as previously described (Wulff et al., 2002; Huang et al., 2004). In brief, a conditional targeting vector was generated from a 7-kb fragment encompassing the entire transcribed region on 12 exons. The neomycin resistance cassette was flanked by two loxP sites and inserted into intron 11. Exons 4–11, which code for the sgk1 kinase domain, were “floxed” by inserting a third loxP site into intron 3. A clone with a recombination between the first and third loxP site (type I recombination) was injected into C57BL/6 blastocytes. Male chimeras were bred to C57BL/6 and 129/SvJ females. Heterozygous SGK1-deficient mice were backcrossed to 129/SvJ wild-type mice (Charles River, Sulzfeld, Germany) for ten generations and then intercrossed to generate homozygous SGK1 knockout mice (sgk1-/-) and their wild type littermates (sgk1+/+).
Anmerkungen

The source is not mentioned.

It is not surprising that the two dissertations have used mice that have been treated identically, and it is efficient to describe this with the same words, but this should have been made transparent.

Sichter
(Hindemith), WiseWoman

[14.] Dsa/Fragment 060 29 - Diskussion
Zuletzt bearbeitet: 2016-08-06 20:45:19 WiseWoman
Boini 2006, Dsa, Fragment, Gesichtet, SMWFragment, Schutzlevel sysop, Verschleierung

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Verschleierung
Bearbeiter
Hindemith
Gesichtet
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Untersuchte Arbeit:
Seite: 60, Zeilen: 29-37
Quelle: Boini 2006
Seite(n): 35, Zeilen: 20ff
The tail cuff method has the advantage to be noninvasive and can provide reproducible results of systolic blood pressure if those precautions are taken into account (Kurtz et al., (2005) Arterioscler Tromb Vasc Biol). Systolic arterial blood pressure was determined by the tail-cuff method (IITC, model 179, Woodland Hills, California, USA) before, 7 weeks and 12 weeks following the initiation of DOCA/high-salt treatment. As reviewed recently, (Meneton P et al., (2000) J Am Soc Neprhol), the tail cuff approach to determine arterial blood pressure requires certain precautions to reduce the stress of the animals, including appropriate training of the mice over multiple days and adequate prewarming to dilate the tail artery. III. 3. Blood pressure: Systolic arterial blood pressure was determined by application of the tail-cuff method. As reviewed recently (Meneton et al., 2000), the tail cuff approach to determine arterial blood pressure requires certain precautions to reduce the stress of the animals, including appropriate training of the mice over multiple days, prewarming to an ambient temperature of 29°C, measurement in a quiet, semidarkend and clean environment, and performance of the measurements by one person and during a defined day time, when blood pressure is stable (between 1-3 PM). All these precautions were taken in the present study. The tail cuff method has the advantage to be noninvasive and can provide reproducible results of systolic blood pressure if those precautions are taken into account (Kurtz et al., 2005).
Anmerkungen

The source is not given.

Sichter
(Hindemith), WiseWoman

[15.] Dsa/Fragment 088 21 - Diskussion
Zuletzt bearbeitet: 2016-08-06 20:50:48 WiseWoman
Boini 2006, Dsa, Fragment, Gesichtet, SMWFragment, Schutzlevel sysop, Verschleierung

Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 88, Zeilen: 21-35
Quelle: Boini 2006
Seite(n): 85, 87, Zeilen: 85: 9-19; 87: 15ff
Enhanced SGK1 expression has been observed in the salt-sensitive Dahl rat (Farjah M. et al., (2003) Hypertension), and moderately enhanced blood pressure is observed in individuals carrying a variant of the SGK1 gene, affecting as many as 5% of unselected Caucasians (Busjahn A. et al., (2002) Hypertension). In the same individuals, increased body mass index (Dieter M. et al., (2004) Obes Res) and a shortening of the Q-T interval (Busjahn A. et al., (2002) Hypertension; Busjahn A and Luft FC., (2003) Cell Physiol Biochem) have been observed. The increased body mass index may be partially due to enhanced stimulation of the intestinal glucose transporter SGLT1 (Dieter M. et al., (2004) Obes Res), the accelerated cardiac repolarization due to enhanced activation of the cardiac K+ channel KCNE1 (Busjahn A. et al., (2004) Cell Physiol Biochem; Embark HM. et al., (2004) Cell Physiol Biochem). Thus excessive stimulation of carriers and channels by SGK1 could account for obesity, hypertension, and shortened cardiac action potential. SGK1 has previously been shown to regulate the ROMK1 channel (Yun CC et al., (2002) J Biol Chem). Moreover, SGK1-dependent ENaC activity is expected to depolarize the apical cell membrane of principal cells, thus favoring K+ secretion. Along those lines enhanced SGK1 expression has been observed in the salt sensitive Dahl rat (Farjah., 2003). In addition, moderately enhanced blood pressure is observed in individuals carrying a variant of the SGK1 gene, affecting as many as 5% of unselected Caucasians (Busjahn et al., 2002). In the same individuals increased body mass index and a shortening of the QT interval (Busjahn et al., 2002; Busjahn and Luft 2003) have been observed. The increased body mass index may be partially due to enhanced stimulation of the intestinal glucose transporter SGLT1 (Dieter et al., 2004), the accelerated cardiac repolarization due to enhanced activation of the cardiac K+ channel KCNE1 (Busjahn et al., 2004; Embark et al., 2003). Thus, altered regulation of carriers and channels by SGK1 could account for the coincidence of obesity, hypertension and altered cardiac action potential (Lang et al., 2003). [...]

[page 87]

[...] SGK1 has previously been demonstrated to regulate the renal outer medullary K+ channel ROMK1 (Yun et al., 2002), and possibly further K+ channels important for renal K+ elimination. Beyond that, SGK1 dependent activity of ENaC is expected to depolarize the apical cell membrane of principal cells thus favoring K+ secretion.

Anmerkungen

The source is not mentioned.

Sichter
(Hindemith), WiseWoman

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