PMID- 24705402
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 63
IP  - 6
DP  - 2014 Jun
TI  - Epidermal growth factor receptor inhibition slows progression of diabetic 
      nephropathy in association with a decrease in endoplasmic reticulum stress and an 
      increase in autophagy.
PG  - 2063-72
LID - 10.2337/db13-1279 [doi]
AB  - Previous studies by us and others have reported renal epidermal growth factor 
      receptors (EGFRs) are activated in models of diabetic nephropathy. In the present 
      study, we examined the effect of treatment with erlotinib, an inhibitor of EGFR 
      tyrosine kinase activity, on the progression of diabetic nephropathy in a type 1 
      diabetic mouse model. Inhibition of renal EGFR activation by erlotinib was 
      confirmed by decreased phosphorylation of EGFR and extracellular signal-related 
      kinase 1/2. Increased albumin/creatinine ratio in diabetic mice was markedly 
      attenuated by erlotinib treatment. Erlotinib-treated animals had less 
      histological glomerular injury as well as decreased renal expression of 
      connective tissue growth factor and collagens I and IV. Autophagy plays an 
      important role in the pathophysiology of diabetes mellitus, and impaired 
      autophagy may lead to increased endoplasmic reticulum (ER) stress and subsequent 
      tissue injury. In diabetic mice, erlotinib-treated mice had evidence of increased 
      renal autophagy, as indicated by altered expression and activity of ATG12, 
      beclin, p62, and LC3A II, hallmarks of autophagy, and had decreased ER stress, as 
      indicated by decreased expression of C/EBP homologous protein, binding 
      immunoglobulin protein, and protein kinase RNA-like ER kinase. The mammalian 
      target of rapamycin (mTOR) pathway, a key factor in the development of diabetic 
      nephropathy and an inhibitor of autophagy, is inhibited by AMP-activated protein 
      kinase (AMPK) activation. Erlotinib-treated mice had activated AMPK and 
      inhibition of the mTOR pathway, as evidenced by decreased phosphorylation of 
      raptor and mTOR and the downstream targets S6 kinase and eukaryotic initiation 
      factor 4B. Erlotinib also led to AMPK-dependent phosphorylation of Ulk1, an 
      initiator of mammalian autophagy. These studies demonstrate that inhibition of 
      EGFR with erlotinib attenuates the development of diabetic nephropathy in type 1 
      diabetes, which is mediated at least in part by inhibition of mTOR and activation 
      of AMPK, with increased autophagy and inhibition of ER stress.
CI  - (c) 2014 by the American Diabetes Association.
FAU - Zhang, Ming-Zhi
AU  - Zhang MZ
AD  - Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 
      ming-zhi.zhang@vanderbilt.edu ray.harris@vanderbilt.edu.
FAU - Wang, Yinqui
AU  - Wang Y
AD  - Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
FAU - Paueksakon, Paisit
AU  - Paueksakon P
AD  - Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN.
FAU - Harris, Raymond C
AU  - Harris RC
AD  - Department of Medicine, Vanderbilt University School of Medicine, Nashville, 
      TNDepartment of Veterans Affairs, Nashville, TN ming-zhi.zhang@vanderbilt.edu 
      ray.harris@vanderbilt.edu.
LA  - eng
GR  - DK-3961/DK/NIDDK NIH HHS/United States
GR  - R01 CA122620/CA/NCI NIH HHS/United States
GR  - DK-95785/DK/NIDDK NIH HHS/United States
GR  - R01 DK095785/DK/NIDDK NIH HHS/United States
GR  - CA-122620/CA/NCI NIH HHS/United States
GR  - DK-62794/DK/NIDDK NIH HHS/United States
GR  - DK-7934/DK/NIDDK NIH HHS/United States
GR  - R01 DK051265/DK/NIDDK NIH HHS/United States
GR  - R01 DK062794/DK/NIDDK NIH HHS/United States
GR  - DK-51265/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140404
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Blood Glucose)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Albuminuria/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/*drug effects
MH  - Blood Glucose/drug effects
MH  - Blood Pressure
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/*drug therapy/physiopathology
MH  - Diabetic Nephropathies/*drug therapy/physiopathology
MH  - Disease Progression
MH  - *Endoplasmic Reticulum Stress/drug effects
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Erlotinib Hydrochloride
MH  - Immunohistochemistry
MH  - Kidney/*pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Quinazolines/*pharmacology
MH  - Signal Transduction
PMC - PMC4030104
EDAT- 2014/04/08 06:00
MHDA- 2014/09/17 06:00
PMCR- 2015/06/01
CRDT- 2014/04/08 06:00
PHST- 2014/04/08 06:00 [entrez]
PHST- 2014/04/08 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - db13-1279 [pii]
AID - 1279 [pii]
AID - 10.2337/db13-1279 [doi]
PST - ppublish
SO  - Diabetes. 2014 Jun;63(6):2063-72. doi: 10.2337/db13-1279. Epub 2014 Apr 4.