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Typus
KomplettPlagiat
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 37, Zeilen: 1ff (entire page)
Quelle: Boini 2006
Seite(n): 19, 20, Zeilen: 19: 17ff; 20: 1ff
[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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Sichter
(Hindemith), WiseWoman

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