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Nierenfunktion Kinase-defizienter Mäuse

von Dr. Diana Sandulache

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[1.] Dsa/Fragment 035 01 - Diskussion
Zuletzt bearbeitet: 2016-08-05 12:54:34 WiseWoman
Boini 2006, Dsa, Fragment, Gesichtet, KomplettPlagiat, SMWFragment, Schutzlevel sysop

Typus
KomplettPlagiat
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 35, Zeilen: 1ff (entire page)
Quelle: Boini 2006
Seite(n): 16, 17, 18, Zeilen: 16: 17ff; 17: 1ff; 18: 1ff
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).

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(Hindemith), WiseWoman


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