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Epithelial sodium channel abundance is decreased by an unfolded protein response induced by hyperosmolality.

Crambert G, Ernandez T, Lamouroux C, Roth I, Dizin E, Martin PY, Féraille E, Hasler U - Physiol Rep (2014)

Bottom Line: Hyperosmotic stress profoundly challenges cellular homeostasis and induces endoplasmic reticulum (ER) stress.Both hyperosmolality and chemical induction of ER stress decreased ENaC expression in vitro.ENaC depletion by either stimulus was abolished by transcriptional inhibition and by the chemical chaperone 4-phenylbutyric acid and was partly abrogated by either PERK or ATF6 silencing.

View Article: PubMed Central - PubMed

Affiliation: UPMC/INSERM/Paris Descartes U1138 CNRS ERL 8228, Equipe 3 Métabolisme et Physiologie Rénale, Centre de Recherche des Cordeliers, Paris, France.

No MeSH data available.


Related in: MedlinePlus

Proposed model of decreased ENaC abundance by hyperosmolality. Increased extracellular osmolality induces transient ER stress and activation of the PERK and ATF6 arms of the UPR. Through a transcriptionally‐mediated mechanism, PERK signaling down‐regulates ENaCα while ATF6 signaling decreases ENaCβ and ENaCγ expression. The effects of PERK and ATF6 signaling on each ENaC subunit were reproduced by thapsigargin (Tg) and tunicamycin (Tun). Although IRE1α activation by hyperosmolality was not detected, chemical induction of its activity attenuated ENaCα expression.
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fig07: Proposed model of decreased ENaC abundance by hyperosmolality. Increased extracellular osmolality induces transient ER stress and activation of the PERK and ATF6 arms of the UPR. Through a transcriptionally‐mediated mechanism, PERK signaling down‐regulates ENaCα while ATF6 signaling decreases ENaCβ and ENaCγ expression. The effects of PERK and ATF6 signaling on each ENaC subunit were reproduced by thapsigargin (Tg) and tunicamycin (Tun). Although IRE1α activation by hyperosmolality was not detected, chemical induction of its activity attenuated ENaCα expression.

Mentions: Interference of ER protein folding and membrane trafficking leads to ER stress (Rutkowski and Kaufman 2004; Ron and Walter 2007). Hyperosmolality affects cellular homeostasis and structural organization (Carpentier et al. 1989; Heuser and Anderson 1989; Ellis and Minton 2006; Choe and Strange 2008; Hasler et al. 2008b; Munishkina et al. 2008; Zhou et al. 2008; Burkewitz et al. 2011; Nunes et al. 2013) and previous observations (Kultz et al. 1998; Zhang et al. 1999; Tian and Cohen 2002; van Balkom et al. 2004; Hoorn et al. 2005; Cai et al. 2006, 2010; Dihazi et al. 2011) strongly suggest that hypertonicity induces ER stress in the renal medulla, consistent with our data. In the present study, we examined how hypertonicity affects the UPR in CD principal cells and how this affects ENaC abundance. As summarized in Figure 7, hypertonicity was found to increase activity of the PERK and ATF6 arms of the UPR. Our data indicate that ENaCα abundance is downregulated by PERK signaling while ENaCβ and ENaCγ abundance in non‐stimulated cells is maintained at low levels by basal ATF6 activity, whose activation by NaCl further decreases abundance of both ENaC subunits.


Epithelial sodium channel abundance is decreased by an unfolded protein response induced by hyperosmolality.

Crambert G, Ernandez T, Lamouroux C, Roth I, Dizin E, Martin PY, Féraille E, Hasler U - Physiol Rep (2014)

Proposed model of decreased ENaC abundance by hyperosmolality. Increased extracellular osmolality induces transient ER stress and activation of the PERK and ATF6 arms of the UPR. Through a transcriptionally‐mediated mechanism, PERK signaling down‐regulates ENaCα while ATF6 signaling decreases ENaCβ and ENaCγ expression. The effects of PERK and ATF6 signaling on each ENaC subunit were reproduced by thapsigargin (Tg) and tunicamycin (Tun). Although IRE1α activation by hyperosmolality was not detected, chemical induction of its activity attenuated ENaCα expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4255800&req=5

fig07: Proposed model of decreased ENaC abundance by hyperosmolality. Increased extracellular osmolality induces transient ER stress and activation of the PERK and ATF6 arms of the UPR. Through a transcriptionally‐mediated mechanism, PERK signaling down‐regulates ENaCα while ATF6 signaling decreases ENaCβ and ENaCγ expression. The effects of PERK and ATF6 signaling on each ENaC subunit were reproduced by thapsigargin (Tg) and tunicamycin (Tun). Although IRE1α activation by hyperosmolality was not detected, chemical induction of its activity attenuated ENaCα expression.
Mentions: Interference of ER protein folding and membrane trafficking leads to ER stress (Rutkowski and Kaufman 2004; Ron and Walter 2007). Hyperosmolality affects cellular homeostasis and structural organization (Carpentier et al. 1989; Heuser and Anderson 1989; Ellis and Minton 2006; Choe and Strange 2008; Hasler et al. 2008b; Munishkina et al. 2008; Zhou et al. 2008; Burkewitz et al. 2011; Nunes et al. 2013) and previous observations (Kultz et al. 1998; Zhang et al. 1999; Tian and Cohen 2002; van Balkom et al. 2004; Hoorn et al. 2005; Cai et al. 2006, 2010; Dihazi et al. 2011) strongly suggest that hypertonicity induces ER stress in the renal medulla, consistent with our data. In the present study, we examined how hypertonicity affects the UPR in CD principal cells and how this affects ENaC abundance. As summarized in Figure 7, hypertonicity was found to increase activity of the PERK and ATF6 arms of the UPR. Our data indicate that ENaCα abundance is downregulated by PERK signaling while ENaCβ and ENaCγ abundance in non‐stimulated cells is maintained at low levels by basal ATF6 activity, whose activation by NaCl further decreases abundance of both ENaC subunits.

Bottom Line: Hyperosmotic stress profoundly challenges cellular homeostasis and induces endoplasmic reticulum (ER) stress.Both hyperosmolality and chemical induction of ER stress decreased ENaC expression in vitro.ENaC depletion by either stimulus was abolished by transcriptional inhibition and by the chemical chaperone 4-phenylbutyric acid and was partly abrogated by either PERK or ATF6 silencing.

View Article: PubMed Central - PubMed

Affiliation: UPMC/INSERM/Paris Descartes U1138 CNRS ERL 8228, Equipe 3 Métabolisme et Physiologie Rénale, Centre de Recherche des Cordeliers, Paris, France.

No MeSH data available.


Related in: MedlinePlus