FOXO1 Plays an Important Role in Enhanced Microvascular Cell Apoptosis and Microvascular Cell Loss in Type 1 and Type 2 Diabetic Rats

Behl, Yugal; Krothapalli, P.; Desta, Tesfahun; Roy, Sayon; Graves, Dana T.

doi:10.2337/db08-0537

Cited by 126 publications

(94 citation statements)

References 35 publications

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“…For example, FOXO1 causes cell cycle arrest and decreased proliferation (Furukawa-Hibi et al, 2005) and regulates transcription of genes involved in gluconeogenesis and adipocyte differentiation (Hiromura et al, 2007). Furthermore, FOXO1 has been implicated in the inflammatory events that contribute to diabetic retinopathy and impair bone formation (Behl et al, 2008(Behl et al, , 2009.…”

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confidence: 99%

Altered Fibroblast Proliferation and Apoptosis in Diabetic Gingival Wounds

Desta

Chino

et al. 2010

J Dent Res

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrActAlthough it is known that diabetes impairs oral wound healing, relatively little is known about the cellular parameters affected, particularly in connective tissue. This study investigated the hypothesis that diabetes impairs connective tissue formation in healing gingiva, and that impaired healing is associated with factors that decrease fibroblast numbers. Full-thickness wounds were created in the palatal gingiva of type 1 and type 2 diabetic and normoglycemic mice. Five days after wounding, diabetic mice had less epithelial wound coverage, less new connective tissue formation, and reduced fibroblast density (p < 0.05). This occurred with increased numbers of caspase-3-and TUNEL-positive fibroblasts, decreased fibroblast proliferation, increased nuclear translocation of the pro-apoptotic transcription factor FOXO1, and increased numbers of polymorphonuclear leukocytes, all of which were significant (p < 0.05). The results suggest that diabetes may decrease fibroblast numbers through increased apoptosis and reduced proliferation, both of which may be mediated through increased activation of FOXO1.

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confidence: 99%

Altered Fibroblast Proliferation and Apoptosis in Diabetic Gingival Wounds

Desta

Chino

et al. 2010

J Dent Res

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“…Indeed, a transcriptional regulation of Ang-2 by FoxO1 has been reported previously [29,30]. FoxO1 plays an important role in the insulin pathway [35,36], and is an apoptotic factor in retinal endothelial cells and pericytes [37,38]. The activity of FoxO1 can be regulated by multiple pathways, such as the insulin pathway though IRS-1 and Akt, the ROS through c-Jun N-terminal kinase (JNK) signaling [35].…”

Section: Discussionmentioning

confidence: 99%

Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

et al. 2018

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Abstract:The pathogenesis of diabetic retinopathy is closely associated with the breakdown of the neurovascular unit including the glial cells. Deficiency of nucleoside diphosphate kinase B (NDPK-B) results in retinal vasoregression mimicking diabetic retinopathy. Increased retinal expression of Angiopoietin-2 (Ang-2) initiates vasoregression. In this study, Müller cell activation, glial Ang-2 expression, and the underlying mechanisms were investigated in streptozotocin-induced diabetic NDPK-B deficient (KO) retinas and Müller cells isolated from the NDPK-B KO retinas. Müller cells were activated and Ang-2 expression was predominantly increased in Müller cells in normoglycemic NDPK-B KO retinas, similar to diabetic wild type (WT) retinas. Diabetes induction in the NDPK-B KO mice did not further increase its activation. Additionally, cultured NDPK-B KO Müller cells were more activated and showed higher Ang-2 expression than WT cells. Müller cell activation and Ang-2 elevation were observed upon high glucose treatment in WT, but not in NDPK-B KO cells. Moreover, increased levels of the transcription factor forkhead box protein O1 (FoxO1) were detected in non-diabetic NDPK-B KO Müller cells. The siRNA-mediated knockdown of FoxO1 in NDPK-B deficient cells interfered with Ang-2 upregulation. These data suggest that FoxO1 mediates Ang-2 upregulation induced by NDPK-B deficiency in the Müller cells and thus contributes to the onset of retinal vascular degeneration.

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“…It can be hypothesize that TNFα contributes to the cascade events in DR: the death of vascular pericytes and endothelial cells microaneurysm and acellular capillary ischemic retina increased HIF-1α and VEGF expression vascular permeability and retinal neovascularization. In addition, TNFα is involved in the DNA binding activity and nuclear translocation of transcription factor FOXO1 in diabetic retina [31]. In retinal endothelia cell cultures, TNFα can regulate expression and cellular localization of ZO-1 and claudin-5, which is mediated by NF-κB and protein kinase (PKC)-delta [32].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Aluminium on the Morphologic Appearance, Viability and Phagocytic Activity of ARPE-19 Cells

Zehetner¹

2014

J Clin Exp Ophthalmol

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Tumor necrosis factor alpha (TNFα) plays an important role in the pathogenesis of diabetic retinopathy (DR). The objective of this study is to investigate the effect of TNFα blockade on complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ) injection or insulin 2 gene point mutation (Akita) in mice. Intravitreal (IVT) and intraperitoneal (IP) injections were used to deliver anti-TNFα antibody and saline control. TUNEL and activated caspase-3 staining were used to examine apoptotic cell death. Transcardially-perfused FITC-ConA and fluorescence microscopy were used to monitor leukocyte adhesion. Trypsin digestion was used to prepare retinal vasculature and quantify acellular capillary. The leakage of 3 H-mannitol into the retina was used to quantify the breakdown of blood-retinal barrier (BRB). TNFα blockade significantly prevented diabetes-related retinal leukostasis. The numbers of caspase 3-positive and TUNEL-positive cells were significantly increased in diabetic retina, but reduced due to anti-TNFα treatment. The increased acellular capillary by diabetes was significantly prevented by anti-TNFα treatment. Diabetes-caused BRB breakdown was prevented by antibody treatment at 3 and 6 months. IVT and IP routes of antibody delivery had similar efficacy and dose response curve. Among the examined dose ranges (1-10 μg/eye for IVT injection and 2-25 mg/kg for IP injection), the antibody inhibited complications of DR in a dose-dependent manner. These results suggest that anti-TNFα therapy is a potential therapeutic treatment for DR.

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FOXO1 Plays an Important Role in Enhanced Microvascular Cell Apoptosis and Microvascular Cell Loss in Type 1 and Type 2 Diabetic Rats

Cited by 126 publications

References 35 publications

Altered Fibroblast Proliferation and Apoptosis in Diabetic Gingival Wounds

Altered Fibroblast Proliferation and Apoptosis in Diabetic Gingival Wounds

Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

The Effect of Aluminium on the Morphologic Appearance, Viability and Phagocytic Activity of ARPE-19 Cells

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