| Authors |
Zhang MZ, Wang Y, Paueksakon P, Harris RC
|
| Submitted By |
Raymond Harris on 4/15/2014 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2014 |
| Date Published |
4/11/2014 |
| Volume : Pages |
63 : 2063 - 2072 |
| PubMed Reference |
|
| Abstract |
Previous studies by us and others have reported renal epidermal growth factor
receptors (EGFRs) are activated in models of diabetic nephropathy. In the
present studies, we examined the effect of treatment with erlotinib, an
inhibitor of EGFR tyrosine kinase activity, on 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.
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