PMID- 22205374
OWN - NLM
STAT- MEDLINE
DCOM- 20120518
LR  - 20211203
IS  - 1421-9670 (Electronic)
IS  - 0250-8095 (Print)
IS  - 0250-8095 (Linking)
VI  - 35
IP  - 1
DP  - 2012
TI  - Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a 
      redox-sensitive mTOR/S6K1 pathway.
PG  - 90-100
LID - 10.1159/000335079 [doi]
AB  - BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) is a serine kinase that 
      regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose 
      activation can lead to glomerular and proximal tubular cell (PTC) injury and 
      associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling 
      pathways that target fibrosis through adherens junctions. Recent data indicate 
      aldosterone signaling through the mineralocorticoid receptor (MR) can activate 
      the mTOR pathway. Further, antagonism of the MR has beneficial effects on 
      proteinuria that occur independent of hemodynamics. METHODS: Accordingly, 
      hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone 
      and proteinuria, and age-matched Sprague-Dawley rats were treated with either a 
      low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone 
      (MR antagonist) or placebo for 3 weeks. RESULTS: Ren2 rats displayed increases in 
      urine levels of the PTC brush border lysosomal enzyme N-acetyl-beta-aminoglycosidase 
      (beta-NAG) in conjunction with reductions in PTC megalin, the apical membrane 
      adherens protein T-cadherin and basolateral alpha-(E)-catenin, and fibrosis. In 
      concert with these abnormalities, Ren2 renal cortical tissue also displayed 
      increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 
      3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose 
      spironolactone had no effect on blood pressure but decreased proteinuria and 
      beta-NAG comparable to a conventional dose of this MR antagonist. Both doses of 
      spironolactone attenuated ultrastructural maladaptive alterations and led to 
      comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased 
      expression of alpha-(E)-catenin, T- and N-cadherin. CONCLUSIONS: Thereby, MR 
      antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling 
      and redox status independent of changes in blood pressure.
CI  - Copyright (c) 2011 S. Karger AG, Basel.
FAU - Whaley-Connell, Adam T
AU  - Whaley-Connell AT
AD  - Harry S. Truman VA Medical Center, Columbia, MO, USA. 
      whaleyconnella@health.missouri.edu
FAU - Habibi, Javad
AU  - Habibi J
FAU - Nistala, Ravi
AU  - Nistala R
FAU - DeMarco, Vincent G
AU  - DeMarco VG
FAU - Pulakat, Lakshmi
AU  - Pulakat L
FAU - Hayden, Melvin R
AU  - Hayden MR
FAU - Joginpally, Tejaswini
AU  - Joginpally T
FAU - Ferrario, Carlos M
AU  - Ferrario CM
FAU - Parrish, Alan R
AU  - Parrish AR
FAU - Sowers, James R
AU  - Sowers JR
LA  - eng
GR  - R01 HL-73101/HL/NHLBI NIH HHS/United States
GR  - R01 AG034154/AG/NIA NIH HHS/United States
GR  - R01 HL073101/HL/NHLBI NIH HHS/United States
GR  - P01 HL051952/HL/NHLBI NIH HHS/United States
GR  - R03 AG040638/AG/NIA NIH HHS/United States
GR  - R-03 AG040638/AG/NIA NIH HHS/United States
GR  - R01 HL107910/HL/NHLBI NIH HHS/United States
GR  - R01 HL-107910/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111224
PL  - Switzerland
TA  - Am J Nephrol
JT  - American journal of nephrology
JID - 8109361
RN  - 0 (Receptors, Mineralocorticoid)
RN  - 27O7W4T232 (Spironolactone)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Albuminuria/metabolism/pathology
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Blood Pressure
MH  - Immunohistochemistry/methods
MH  - Kidney Tubules/*drug effects
MH  - Male
MH  - Microscopy, Electron, Transmission/methods
MH  - Oxidation-Reduction
MH  - Oxidative Stress
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Mineralocorticoid/*metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Spironolactone/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3316484
EDAT- 2011/12/30 06:00
MHDA- 2012/05/19 06:00
PMCR- 2013/01/01
CRDT- 2011/12/30 06:00
PHST- 2011/09/12 00:00 [received]
PHST- 2011/11/12 00:00 [accepted]
PHST- 2011/12/30 06:00 [entrez]
PHST- 2011/12/30 06:00 [pubmed]
PHST- 2012/05/19 06:00 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - 000335079 [pii]
AID - ajn0035-0090 [pii]
AID - 10.1159/000335079 [doi]
PST - ppublish
SO  - Am J Nephrol. 2012;35(1):90-100. doi: 10.1159/000335079. Epub 2011 Dec 24.