PMID- 28861610
OWN - NLM
STAT- MEDLINE
DCOM- 20190123
LR  - 20211204
IS  - 1432-2013 (Electronic)
IS  - 0031-6768 (Linking)
VI  - 470
IP  - 2
DP  - 2018 Feb
TI  - Inhibitors of the proteasome stimulate the epithelial sodium channel (ENaC) 
      through SGK1 and mimic the effect of aldosterone.
PG  - 295-304
LID - 10.1007/s00424-017-2060-5 [doi]
AB  - The epithelial sodium channel (ENaC) marks the tightly regulated, rate-limiting 
      step of sodium re-absorption in the aldosterone-sensitive distal nephron (ASDN). 
      Stimulation of ENaC activity by aldosterone involves the serum and 
      glucocorticoid-induced kinase 1 (SGK1) and is mediated via complex mechanisms 
      including inhibition of channel retrieval. Retrieved channels may be recycled or 
      degraded, e.g. by the proteasomal pathway. The aim of the present study was to 
      investigate whether inhibitors of the proteasome affect ENaC activity and surface 
      expression, and to explore a possible involvement of SGK1. Short circuit current 
      (I (SC)) measurements were performed on confluent mCCD(cl1) murine cortical 
      collecting duct cells to investigate the effect of two distinct proteasomal 
      inhibitors, MG132 and bortezomib, on amiloride-sensitive ENaC-mediated I (SC). 
      Both inhibitors robustly stimulated amiloride-sensitive I (SC). The time course 
      and magnitude of the stimulatory effect of the proteasomal inhibitors on I (SC) 
      were similar to those of aldosterone. Both, MG132 and aldosterone, significantly 
      increased the abundance of beta-ENaC at the cell surface. SGK1 activity was assessed 
      by monitoring the phosphorylation of a downstream target, NDRG1, and was found to 
      be increased by MG132. Importantly, inhibiting SGK1 activity prevented not only 
      the stimulatory effect of aldosterone but also that of proteasomal inhibition. In 
      conclusion, these data suggest that ENaC stimulation following proteasomal 
      inhibition is due to an accumulation of active SGK1 resulting in increased 
      expression of ENaC at the cell surface. Thus, inhibition of the proteasome mimics 
      SGK1-dependent stimulation of ENaC by aldosterone.
FAU - Mansley, Morag K
AU  - Mansley MK
AD  - Institut fur Zellulare und Molekulare Physiologie, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany.
FAU - Korbmacher, Christoph
AU  - Korbmacher C
AUID- ORCID: 0000-0003-2127-4185
AD  - Institut fur Zellulare und Molekulare Physiologie, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. 
      christoph.korbmacher@fau.de.
FAU - Bertog, Marko
AU  - Bertog M
AD  - Institut fur Zellulare und Molekulare Physiologie, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany.
LA  - eng
GR  - 3.3-GRO/1143730 STP/Alexander von Humboldt-Stiftung/International
GR  - PDOK-74-10/Bayerische Forschungsstiftung/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170831
PL  - Germany
TA  - Pflugers Arch
JT  - Pflugers Archiv : European journal of physiology
JID - 0154720
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Epithelial Sodium Channel Blockers)
RN  - 0 (Epithelial Sodium Channels)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (N-myc downstream-regulated gene 1 protein)
RN  - 0 (Proteasome Inhibitors)
RN  - 4964P6T9RB (Aldosterone)
RN  - 7DZO8EB0Z3 (Amiloride)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
SB  - IM
MH  - Aldosterone/*pharmacology
MH  - Amiloride/pharmacology
MH  - Animals
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line
MH  - Epithelial Sodium Channel Blockers/pharmacology
MH  - Epithelial Sodium Channels/*metabolism
MH  - Immediate-Early Proteins/*metabolism
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Kidney Tubules, Collecting/cytology/drug effects/metabolism
MH  - Mice
MH  - Proteasome Inhibitors/*pharmacology
MH  - Protein Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Aldosterone
OT  - ENaC
OT  - MG132
OT  - Proteasome
OT  - Renal collecting duct cells
OT  - SGK1
EDAT- 2017/09/02 06:00
MHDA- 2019/01/24 06:00
CRDT- 2017/09/02 06:00
PHST- 2017/06/02 00:00 [received]
PHST- 2017/08/21 00:00 [accepted]
PHST- 2017/08/17 00:00 [revised]
PHST- 2017/09/02 06:00 [pubmed]
PHST- 2019/01/24 06:00 [medline]
PHST- 2017/09/02 06:00 [entrez]
AID - 10.1007/s00424-017-2060-5 [pii]
AID - 10.1007/s00424-017-2060-5 [doi]
PST - ppublish
SO  - Pflugers Arch. 2018 Feb;470(2):295-304. doi: 10.1007/s00424-017-2060-5. Epub 2017 
      Aug 31.