PMID- 24203997
OWN - NLM
STAT- MEDLINE
DCOM- 20140508
LR  - 20220318
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 25
IP  - 3
DP  - 2014 Mar
TI  - Activation of mTORC1 in collecting ducts causes hyperkalemia.
PG  - 534-45
LID - 10.1681/ASN.2013030225 [doi]
AB  - Mutation of TSC (encoding tuberous sclerosis complex protein) and activation of 
      mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of 
      several renal diseases, such as diabetic nephropathy and polycystic kidney 
      disease. However, the role of mTOR in renal potassium excretion and hyperkalemia 
      is not known. We showed that mice with collecting-duct (CD)-specific ablation of 
      TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) activation in the CD and 
      demonstrated features of pseudohypoaldosteronism, including hyperkalemia, 
      hyperaldosteronism, and metabolic acidosis. mTORC1 activation caused endoplasmic 
      reticulum stress, columnar cell lesions, and dedifferentiation of CD cells with 
      loss of aquaporin-2 and epithelial-mesenchymal transition-like phenotypes. Of 
      note, mTORC1 activation also reduced the expression of serum- and 
      glucocorticoid-inducible kinase 1, a crucial regulator of potassium homeostasis 
      in the kidney, and decreased the expression and/or activity of epithelial sodium 
      channel-alpha, renal outer medullary potassium channel, and Na(+), K(+)-ATPase in the 
      CD, which probably contributed to the aldosterone resistance and hyperkalemia in 
      these mice. Rapamycin restored these phenotypic changes. Overall, this study 
      identifies a novel function of mTORC1 in regulating potassium homeostasis and 
      demonstrates that loss of TSC1 and activation of mTORC1 results in 
      dedifferentiation and dysfunction of the CD and causes hyperkalemia. The CDTsc1KO 
      mice provide a novel model for hyperkalemia induced exclusively by dysfunction of 
      the CD.
FAU - Chen, Zhenguo
AU  - Chen Z
AD  - Department of Cell Biology and.
FAU - Dong, Heling
AU  - Dong H
FAU - Jia, Chunhong
AU  - Jia C
FAU - Song, Qiancheng
AU  - Song Q
FAU - Chen, Juan
AU  - Chen J
FAU - Zhang, Yue
AU  - Zhang Y
FAU - Lai, Pinglin
AU  - Lai P
FAU - Fan, Xiaorong
AU  - Fan X
FAU - Zhou, Xuan
AU  - Zhou X
FAU - Liu, Miao
AU  - Liu M
FAU - Lin, Jun
AU  - Lin J
FAU - Yang, Cuilan
AU  - Yang C
FAU - Li, Ming
AU  - Li M
FAU - Gao, Tianming
AU  - Gao T
FAU - Bai, Xiaochun
AU  - Bai X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131107
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Epithelial Sodium Channels)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Kcnj1 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
RN  - EC 7.2.2.13 (Sodium-Potassium-Exchanging ATPase)
RN  - RWP5GA015D (Potassium)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Dedifferentiation
MH  - Endoplasmic Reticulum Stress
MH  - Epithelial Sodium Channels/metabolism
MH  - Female
MH  - Homeostasis
MH  - Hyperkalemia/*etiology
MH  - Immediate-Early Proteins/metabolism
MH  - Kidney Tubules, Collecting/*physiology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes/*metabolism
MH  - Phenotype
MH  - Potassium/*metabolism
MH  - Potassium Channels, Inwardly Rectifying/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Sirolimus
MH  - Sodium-Potassium-Exchanging ATPase/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/*metabolism
PMC - PMC3935580
EDAT- 2013/11/10 06:00
MHDA- 2014/05/09 06:00
PMCR- 2015/03/01
CRDT- 2013/11/09 06:00
PHST- 2013/11/09 06:00 [entrez]
PHST- 2013/11/10 06:00 [pubmed]
PHST- 2014/05/09 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - ASN.2013030225 [pii]
AID - 2013030225 [pii]
AID - 10.1681/ASN.2013030225 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2014 Mar;25(3):534-45. doi: 10.1681/ASN.2013030225. Epub 2013 
      Nov 7.