PMID- 23557706
OWN - NLM
STAT- MEDLINE
DCOM- 20131001
LR  - 20220317
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 62
IP  - 8
DP  - 2013 Aug
TI  - Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in 
      diabetic renal injury.
PG  - 2935-47
LID - 10.2337/db12-1504 [doi]
AB  - Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin 
      that eventuates in kidney fibrosis. Pharmacological doses of the mammalian target 
      of rapamycin (mTOR) inhibitor rapamycin reduce albuminuria in diabetes. We 
      explored the hypothesis that mTOR mediates podocyte injury in diabetes. High 
      glucose (HG) induces apoptosis of podocytes, inhibits AMP-activated protein 
      kinase (AMPK) activation, inactivates tuberin, and activates mTOR. HG also 
      increases the levels of Nox4 and Nox1 and NADPH oxidase activity. Inhibition of 
      mTOR by low-dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase 
      activity, and podocyte apoptosis. Inhibition of mTOR had no effect on AMPK or 
      tuberin phosphorylation, indicating that mTOR is downstream of these signaling 
      molecules. In isolated glomeruli of OVE26 mice, there is a similar decrease in 
      the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 
      and NADPH oxidase activity. Inhibition of mTOR by a small dose of rapamycin 
      reduces podocyte apoptosis and attenuates glomerular injury and albuminuria. Our 
      data provide evidence for a novel function of mTOR in Nox4-derived reactive 
      oxygen species generation and podocyte apoptosis that contributes to urinary 
      albumin excretion in type 1 diabetes. Thus, mTOR and/or NADPH oxidase inhibition 
      may represent a therapeutic modality of diabetic kidney disease.
FAU - Eid, Assaad A
AU  - Eid AA
AD  - Department of Medicine, South Texas Veterans Healthcare System and the University 
      of Texas Health Science Center, San Antonio, Texas, USA. ae49@aub.edu.lb
FAU - Ford, Bridget M
AU  - Ford BM
FAU - Bhandary, Basant
AU  - Bhandary B
FAU - de Cassia Cavaglieri, Rita
AU  - de Cassia Cavaglieri R
FAU - Block, Karen
AU  - Block K
FAU - Barnes, Jeffrey L
AU  - Barnes JL
FAU - Gorin, Yves
AU  - Gorin Y
FAU - Choudhury, Goutam Ghosh
AU  - Choudhury GG
FAU - Abboud, Hanna E
AU  - Abboud HE
LA  - eng
GR  - R01 DK033665/DK/NIDDK NIH HHS/United States
GR  - R01-DK-50190/DK/NIDDK NIH HHS/United States
GR  - R01 DK079996/DK/NIDDK NIH HHS/United States
GR  - R01 DK050190/DK/NIDDK NIH HHS/United States
GR  - DK-R01-078971/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130404
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Ribonucleotides)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - F0X88YW0YK (AICA ribonucleotide)
RN  - IY9XDZ35W2 (Glucose)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenylate Kinase/metabolism
MH  - Aminoimidazole Carboxamide/analogs & derivatives/pharmacology
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Cell Line
MH  - Diabetic Nephropathies/*metabolism
MH  - Glucose/*pharmacology
MH  - Hypoglycemic Agents/pharmacology
MH  - Mice
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/*metabolism
MH  - Phosphorylation/drug effects
MH  - Podocytes/drug effects/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Ribonucleotides/pharmacology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3717863
EDAT- 2013/04/06 06:00
MHDA- 2013/10/18 06:00
PMCR- 2014/08/01
CRDT- 2013/04/06 06:00
PHST- 2013/04/06 06:00 [entrez]
PHST- 2013/04/06 06:00 [pubmed]
PHST- 2013/10/18 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - db12-1504 [pii]
AID - 1504 [pii]
AID - 10.2337/db12-1504 [doi]
PST - ppublish
SO  - Diabetes. 2013 Aug;62(8):2935-47. doi: 10.2337/db12-1504. Epub 2013 Apr 4.