Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization

Kondo, Tatsuya; Vicent, David; Suzuma, Kiyoshi; Yanagisawa, Masashi; King, George L.; Holzenberger, Martin; Kahn, C. Ronald

doi:10.1172/jci200317455

Cited by 178 publications

(76 citation statements)

References 43 publications

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“…Inhibition of IGF-IR signaling has been shown to reduce VEGF production in tumor cells (36,37) and to interfere with retinal neovascularization through its effect on endothelial cells (38). Our data provide further support that these two pathways likely also interact in the SW527 tumor model.…”

Section: Induces Dynamic Changes Of Tumor Transcriptional Profilessupporting

confidence: 66%

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Shang¹,

Mao²,

Batson³

et al. 2008

Molecular Cancer Therapeutics

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The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor downregulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti -vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging. [Mol Cancer Ther 2008;7(9):2599 -608]

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Section: Induces Dynamic Changes Of Tumor Transcriptional Profilessupporting

confidence: 66%

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Shang¹,

Mao²,

Batson³

et al. 2008

Molecular Cancer Therapeutics

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“…This is supported by our previous observation that mice with a vascular endothelial cell specific knock-out of the insulin receptor (VENIRKO) are protected from retinal neovascularization (7). Furthermore, in general, rates of development of retinopathy are somewhat lower in patients with insulin-resistant type 2 diabetes than in those with insulin-deficient type 1 diabetes (8,12).…”

supporting

confidence: 55%

“…Clinical studies have indicated that hyperglycemia and poor metabolic control are important factors in the development of diabetic retinopathy (1,2). Multiple mechanisms have been implicated, including relative hypoxia in retina, resulting in the induction of vascular endothelial growth factor (VEGF) 1 and other vascular mediators that stimulate proliferation of retinal endothelial cells in preretinal area (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Altered Insulin Signaling in Retinal Tissue in Diabetic States

Kondo

Kahn

2004

Journal of Biological Chemistry

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Both type 1 and type 2 diabetes can lead to altered retinal microvascular function and diabetic retinopathy. Insulin signaling may also play a role in this process, and mice lacking insulin receptors in endothelial cells are protected from retinal neovascularization. To define the role of diabetes in retinal function, we compared insulin signaling in the retinal vasculature of mouse models of type 1 (streptozotocin) and type 2 diabetes (ob/ob). In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. In both mice, Phosphatidylinositol 3,4,5-trisphosphate generation by acute insulin stimulation was enhanced in retinal endothelial cells. On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. HIF-1␣ and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. Furthermore, insulin signaling in retinal endothelial cells is differentially altered in diabetes and is also differentially regulated from insulin signaling in classical target tissues such as liver.

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“…Tissuespecific (Cre/lox) deletion of the IR in various tissues shows distinct phenotypes (17), including dyslipidemia in muscle (18), impaired glucose tolerance in adipose tissues (19), moderate insulin resistance and transient hyperglycemia in liver (20), impaired glucose tolerance in pancreatic ␤-cells (21), ␤-cell failure in brown adipocytes (22), obesity and reduced fertility in brain tissues (23), and protection against retinal neovascularization in vascular endothelial cells (24). The functional role of IRs in retina or photoreceptor cells is not known.…”

Section: Insulin Receptor (Ir)mentioning

confidence: 99%

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Rajala

Tanito

et al. 2008

Journal of Biological Chemistry

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113

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Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/lox system to specifically inactivate the IR gene in rod photoreceptors. Rodspecific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to lightinduced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection. Insulin receptor (IR)2 signaling provides a trophic signal for transformed retinal neurons in culture (1), but the role of the IR in vivo is unknown. IR activation has been shown to rescue retinal neurons from apoptosis through a phosphoinositide 3-kinase (PI3K) cascade (1). We previously reported that light induces tyrosine phosphorylation of the retinal IR and that this activation leads to the binding of PI3K to rod outer segment (ROS) membranes (2). More recently, we demonstrated that IR activation is mediated through the G-protein-coupled receptor rhodopsin (3). IR signaling is also involved in 17␤-estradiolmediated neuroprotection in the retina (4). Recent evidence suggests a down-regulation of IR kinase activity in diabetic retinopathy that is associated with the deregulation of downstream signaling molecules (5). Deletion of several downstream effector molecules of the IR signaling pathway, such as IRS-2 (6), Akt2 (7), and Bcl-xl (8), in the retina resulted in a photoreceptor degeneration phenotype. These studies clearly indicate the importance of the IR signaling pathway in the retina.The IR is highly conserved, and the high degree of IR signaling homology between Caenorhabditis elegans, Drosophila, and humans suggests functional conservation in mammalian retina. The IR regulates neuronal survival in C. elegans (9). In Drosophila, the IR serves an important function to guide retinal photoreceptor axons from the retina to the brain during development (10), and the IR influences the size and number of photoreceptors (11). The lack of IR activation leads to neurod...

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Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization

Cited by 178 publications

References 43 publications

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Altered Insulin Signaling in Retinal Tissue in Diabetic States

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

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