The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy

Zhou, Ti; Kk, Zhou; Lee, Kyung Hwa; Gao, Guoquan; Lyons, Timothy J.; Kowluru, Renu A.; Ma, Jichi

doi:10.1007/s00125-010-1943-1

Cited by 73 publications

(72 citation statements)

References 46 publications

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“…We injected 2F1 antibody, which binds to the ligand-binding domain of LRP6 and blocks WNT pathway activation [30], into Akita mice; the same dose of non-specific mouse IgG was used as the negative control. Western blot analysis showed that the accumulation of β-catenin in the kidneys of Akita mice was Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As there are multiple WNT ligands and FZD receptors, but only two co-receptors-LRP5 and LRP6-we used an antibody specific for the ligand-binding domain of LRP6 to inhibit WNT signalling [30]. Injection of this antibody into Akita mice inhibited the activation of the WNT pathway and ameliorated diabetic nephropathy as shown by fibrogenic factor production, extracellular matrix accumulation and proteinuria.…”

Section: Discussionmentioning

confidence: 99%

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Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

et al. 2011

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Aims/hypothesis The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy. Methods Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabetic rats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis. Results Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabetic rats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice. Conclusions/interpretation The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

et al. 2011

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“…The Wnt pathway is essential for the early development of eukaryotic organisms and is involved in cell proliferation, differentiation, and oncogenesis (Kitazoe et al, 2010). Lipid peroxidation products activate the canonical Wnt pathway through oxidative stress (Zhou et al, 2011). The insulin signaling pathway controls the synthesis and accumulation of lipids in the mammalian liver.…”

Section: Discussionmentioning

confidence: 99%

Differentially expressed genes in the liver of lean and fat chickens

He¹,

Wang²,

Leng³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This study aimed to investigate gene expression in the chicken liver for lean and fat broiler lines. Birds used in this study were 2 and 4 weeks of age; they were derived from the 14th generation of Northeast Agricultural University broiler lines, which were divergently selected based on abdominal fat content. Chicken Genome Arrays were used to screen differentially expressed genes in the liver tissue from lean and fat birds. At 2 and 4 weeks of age, 770 and 452 genes were differentially expressed between the 2 lines, respectively. The differentially expressed genes were involved in Wnt, insulin signaling, and cell cycle pathways. At 2 and 4 weeks, 42 shared, differentially expressed genes were revealed by the analysis. We speculate that these genes might regulate chicken lipid metabolism.

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“…Similar or higher concentrations have been used in the past by others and by ourselves for studies on various cell types. 14,15,31,[35][36][37][38][39] Cell Viability Assay …”

Section: Ldl Concentrations In Cell Culturementioning

confidence: 99%

Oxidative and Endoplasmic Reticulum Stresses Mediate Apoptosis Induced by Modified LDL in Human Retinal Müller Cells

Wu¹,

Yang

Elliott

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We previously showed that extravasated, modified LDL is implicated in pericyte loss in diabetic retinopathy (DR). Here, we investigate whether modified LDL induces apoptosis in retinal Müller glial cells. METHODS. Cultured human retinal Müller cells (MIO-M1) were treated with highly oxidized glycated LDL (HOG-LDL, 200 mg protein/L) or native LDL (N-LDL, 200 mg protein/L) for up to 24 hours with or without pretreatment with N-acetyl-cysteine (NAC, a blocker of oxidative stress) and 4-phenylbutyrate (4-PBA, a blocker of endoplasmic reticulum [ER] stress). Effects of HOG-LDL on cell viability, apoptosis, oxidative stress, and ER stress were assessed by cell viability, TUNEL, and Western blot assays. In separate experiments, Müller cells were treated with 7-ketocholesterol (7-KC, 5-20 lM) or 4-hydroxynonenal (4-HNE, 5-40 lM) for up to 24 hours. The same markers were measured.RESULTS. HOG-LDL induced apoptosis (decreased cell viability, increased TUNEL staining, increased expression of cleaved PARP, cleaved caspase-3, and BAX; decreased Bcl-2), oxidative stress (increased NOX4 and antioxidant enzymes, catalase, and superoxide dismutase 2), and ER stress (increased phospho-eIF2a, KDEL, ATF6, and CHOP). Pretreatment with NAC or 4-PBA partially attenuated apoptosis. In addition. NAC attenuated activation of ER stress. Similar to HOG-LDL, 7KC, and 4HNE also induced apoptosis, oxidative stress, and ER stress.CONCLUSIONS. Our data suggest that extravasated, modified lipoproteins may be implicated in apoptotic Müller cell death, acting at least partially via enhanced levels of oxidative and ER stresses. They support our main hypothesis that, in addition to hyperglycemia, extravasated and oxidized LDL is an important insult to the diabetic retina. (Invest Ophthalmol Vis Sci. 2012;53:4595-4604 In previous work, we proposed that in addition to hyperglycemia, extravasation of plasma lipoproteins through leaking blood retinal barriers (BRB) and their subsequent modification (glycation, oxidation) are important in the propagation of DR. 12-18 Several lines of evidence support this concept. Clinical studies indicate that dyslipidemia is associated with the severity of DR In particular, DR is positively associated with serum levels of LDL, apolipoprotein B (ApoB), and LDL particle concentration in type 1 diabetic patients. 13,[19][20][21] However, dyslipidemia in the absence of diabetes does not cause retinal injury, and we suggest that breakdown of the BRB is the critical factor. Using immunohistochemistry (for ApoB and oxidized LDL [ox-LDL]), we identified the presence of intraretinal modified LDL in type 2 diabetic patients who had not yet developed clinical DR, with larger amounts proportionate to disease severity in patients with clinical DR This staining initially surrounded the inner retinal capillaries. We also confirmed the absence of ApoB and ox-LDL in normal human retina. 16 In ex vivo studies, ox-LDL was associated with apoptotic figures in human diabetic retinas. 16 In more severe DR cases with proliferative D...

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The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy

Cited by 73 publications

References 46 publications

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Differentially expressed genes in the liver of lean and fat chickens

Oxidative and Endoplasmic Reticulum Stresses Mediate Apoptosis Induced by Modified LDL in Human Retinal Müller Cells

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