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2014 ; 63
(6
): 2063-72
Nephropedia Template TP
gab.com Text
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English Wikipedia
Epidermal growth factor receptor inhibition slows progression of diabetic
nephropathy in association with a decrease in endoplasmic reticulum stress and an
increase in autophagy
#MMPMID24705402
Zhang MZ
; Wang Y
; Paueksakon P
; Harris RC
Diabetes
2014[Jun]; 63
(6
): 2063-72
PMID24705402
show ga
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.