Regulation of IGF-I Signaling in Retinal Endothelial Cells by Hyperglycemia

Miller, Emily; Capps, Byron E.; Sanghani, Ravi; Clemmons, David R.; Maile, Laura A.

doi:10.1167/iovs.07-0014

Cited by 22 publications

(50 citation statements)

References 41 publications

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“…14 Little is known of the mechanism of action of β3 and angiogenesis. However, a recent study by Miller et al 23 showed that retinal endothelial cells in hyperglycemic conditions upregulate β3 ligand binding leading to an increase in its activation state, as measured by tyrosine phosphorylation, contributing to an enhanced responsiveness of retinal endothelial cells to insulin growth factor-I. In future, antagonists to the β3 integrin subunit may be used in models to assess its efficacy in inhibiting the angiogenic response.…”

Section: Discussionmentioning

confidence: 99%

Expression of integrins in human proliferative diabetic retinopathy membranes

Ning

Cui

Maberley

et al. 2008

Canadian Journal of Ophthalmology

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Section: Discussionmentioning

confidence: 99%

Expression of integrins in human proliferative diabetic retinopathy membranes

Ning

Cui

Maberley

et al. 2008

Canadian Journal of Ophthalmology

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“…Endothelial cells express ␣v␤3, Src, p66 shc , and SHPS-1, which are required for studying SHPS-1 signaling complex formation and modulation of IGF-I signal transduction in hyperglycemia. In addition, they have been shown to respond to hyperglycemia by increasing their sensitivity to IGF-I stimulation (28,29). Therefore, we believe that this mechanism at least is applicable to specific cell types that have the capability to respond to hyperglycemic and/or oxidative stress with an increase in proliferation in response to IGF-I.…”

Section: P66mentioning

confidence: 95%

“…We chose endothelial cells because they express ␣V␤3, Src, p66 shc , and SHPS-1, the major components affecting SHPS-1 complex formation and IGF-I signal transduction, and they have been shown to respond to hyperglycemia by increasing their sensitivity to IGF-I stimulation (28,29). Similar to pSMC, IGF-I stimulated p66…”

Section: Sion Of P66mentioning

confidence: 99%

p66 Inhibits Insulin-like Growth Factor-I Signaling via Direct Binding to Src through Its Polyproline and Src Homology 2 Domains, Resulting in Impairment of Src Kinase Activation

Shen

Clemmons

2010

Journal of Biological Chemistry

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p66shc is increased in response to cell stress, and these increases regulate growth factor actions. These studies were conducted to determine how p66shc alters IGF-I-stimulated Src activation, leading to decreased IGF-I actions. Our results show that p66 shc binds to Src through a polyproline sequence motif contained in the CH2 domain, a unique domain in p66shc , and IGF-I stimulates this interaction. Disruption of this interaction using a synthetic peptide containing the p66 shc polyproline domain or expression of a p66shc mutant containing substitutions for the proline residues (P47A/P48A/P50A) resulted in enhanced Src kinase activity, p52shc phosphorylation, MAPK activation, and cell proliferation in response to IGF-I. To determine the mechanism of inhibition, the full-length CH2 domain and intact p66shc were tested for their ability to directly inhibit Src kinase activation in vitro. The CH2 domain peptide was clearly inhibitory, but full-length p66 shc had a greater effect. Deletion of the C-terminal Src homology 2 domain in p66 shc reduced its ability to inhibit Src kinase activation. These findings demonstrate that p66 shc utilizes a novel mechanism for modulating Src kinase activation and that this interaction is mediated through both its collagen homologous region 2 and Src homology 2 domains.

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“…This leads to an increase in ligand occupancy of ␣V␤3, which in turn stimulates phosphorylation of the ␤3 -subunit (14). Blocking ␤3-subunit phosphorylation has been shown to inhibit hyperglycemia-induced changes in capillary permeability in vitro (15). Additionally, inhibition of ␣V␤3 in vascular endothelial and smooth muscle cells leads to decreased stimulation of both the MAPK and phosphoinoside-3 kinase pathways in response to IGF-I stimulation (14,15).…”

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confidence: 99%

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

et al. 2014

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Hyperglycemia stimulates secretion of αVβ3 ligands from vascular cells, including endothelial cells, resulting in activation of the αVβ3 integrin. This study determined whether blocking ligand occupancy of αVβ3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab)2 fragment of an antibody directed against the extracellular domain of the β3-subunit, and 10 received a control IgG F(ab)2 for 18 weeks. Nondiabetic pigs excreted 115 ± 50 μg of protein/mg creatinine compared with control F(ab)2-treated diabetic animals (218 ± 57 μg/mg), whereas diabetic animals treated with the anti-β3 F(ab)2 excreted 119 ± 55 μg/mg (P < .05). Mesangial volume/glomerular volume increased to 21 ± 2.4% in control-treated diabetic animals compared with 14 ± 2.8% (P < .01) in animals treated with active antibody. Diabetic animals treated with control F(ab)2 had significantly less glomerular podocin staining compared with nondiabetic animals, and this decrease was attenuated by treatment with anti-β3 F(ab)2. Glomerular basement membrane thickness was increased in the control, F(ab)2-treated diabetic animals (212 ± 14 nm) compared with nondiabetic animals (170 ± 8.8 nm), but it was unchanged (159.9 ± 16.4 nm) in animals receiving anti-β3 F(ab)2. Podocyte foot process width was greater in control, F(ab)2-treated, animals (502 ± 34 nm) compared with animals treated with the anti-β3 F(ab)2 (357 ± 47 nm, P < .05). Renal β3 tyrosine phosphorylation decreased from 13 934 ± 6437 to 6730 ± 1524 (P < .01) scanning units in the anti-β3-treated group. We conclude that administration of an antibody that inhibits activation of the β3-subunit of αVβ3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy, suggesting that it may have utility in preventing the progression of this disease complication.

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Regulation of IGF-I Signaling in Retinal Endothelial Cells by Hyperglycemia

Abstract: This study demonstrates that hyperglycemic conditions enhance the response of RECs to IGF-I by increasing the association of IAP with SHPS-1 permitting the formation of the SHPS-1-Shc signaling complex, which is required for the proliferative response to IGF-I.

Cited by 22 publications

References 41 publications

Expression of integrins in human proliferative diabetic retinopathy membranes

Expression of integrins in human proliferative diabetic retinopathy membranes

p66 Inhibits Insulin-like Growth Factor-I Signaling via Direct Binding to Src through Its Polyproline and Src Homology 2 Domains, Resulting in Impairment of Src Kinase Activation

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

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