High glucose-induced phospholipase D activity in retinal pigment epithelium cells: New insights into the molecular mechanisms of diabetic retinopathy

Tenconi, Paula Estefanía; Bermúdez, Vicente; Oresti, Gerardo Martín; Giusto, Norma M.; Salvador, Gabriela Alejandra; Mateos, Melina Valeria

doi:10.1016/j.exer.2019.04.028

Cited by 29 publications

(34 citation statements)

References 65 publications

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“…In the inner retina, the high glucose concentrations are shown to increase the permeability and decrease the viability of endothelial cells [1,27]. Although the effects of a high glucose concentration in the inner retina have been carefully assessed, there has been only few studies on its effects in the outer retina [1,2,3,6,7,8,10]. According to our knowledge, there are no previous publications in which the maturation of hiPSC-RPEs derived from type 2 diabetics and healthy controls have been assessed in high or normal glucose concentration in the presence or absence of added insulin.…”

Section: Discussionmentioning

confidence: 99%

“…The vascular leakage from these newly formed vessels can lead to swelling of the macula, and hence to the macular edema, which is the most common cause of blindness in diabetic patients [1,5]. Endothelial pathology in DR has been characterized in detail, but the effects in the outer retina, in retinal pigment epithelium (RPE), has drawn rather little attention [1,2,3,5,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

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Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Kiamehr

Klettner

Richert

et al. 2019

IJMS

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In diabetic patients, high blood glucose induces alterations in retinal function and can lead to visual impairment due to diabetic retinopathy. In immortalized retinal pigment epithelial (RPE) cultures, high glucose concentrations are shown to lead to impairment in epithelial barrier properties. For the first time, the induced pluripotent stem-cell-derived retinal pigment epithelium (hiPSC-RPE) cell lines derived from type 2 diabetics and healthy control patients were utilized to assess the effects of glucose concentration on the cellular functionality. We show that both type 2 diabetic and healthy control hiPSC-RPE lines differentiate and mature well, both in high and normal glucose concentrations, express RPE specific genes, secrete pigment epithelium derived factor, and form a polarized cell layer. Here, type 2 diabetic hiPSC-RPE cells had a decreased barrier function compared to controls. Added insulin increased the epithelial cell layer tightness in normal glucose concentrations, and the effect was more evident in type 2 diabetics than in healthy control hiPSC-RPE cells. In addition, the preliminary functionality assessments showed that type 2 diabetic hiPSC-RPE cells had attenuated autophagy detected via ubiquitin-binding protein p62/Sequestosome-1 (p62/SQSTM1) accumulation, and lowered pro- matrix metalloproteinase 2 (proMMP2) as well as increased pro-MMP9 secretion. These results suggest that the cellular ability to tolerate stress is possibly decreased in type 2 diabetic RPE cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Kiamehr

Klettner

Richert

et al. 2019

IJMS

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“…Recent studies found that methyltransferase-like 3 (METTL3) mediated m 6 A modifications were closely related with the development of type 2 diabetes mellitus (T2DM) [6], but it was still unclear whether METTL3 regulated DR progression. The high-glucose treated retinal pigment epithelium (RPE) cells were used in this study as the in vitro models for DR research according to the previous studies [36][37][38]. The results showed that METTL3 was low expressed in the peripheral venous blood samples collected from T2DM patients compared to the normal volunteers.…”

Section: Figure 4 High-glucose Inhibited Rpe Cell Viability By Regulmentioning

confidence: 99%

Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/Akt signaling cascade through DGCR8

Fan

et al. 2020

Aging

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Methyltransferase-like protein 3 (METTL3) regulates multiple cell functions and diseases by modulating N 6methyladenosine (m 6 A) modifications. However, it is still unclear whether METTL3 involves in the pathogenesis of diabetic retinopathy (DR). In the present study, we found that high-glucose inhibited RPE cell proliferation, promoted cell apoptosis and pyroptosis in a time-dependent manner. In addition, both METTL3 mRNA and miR-25-3p were low-expressed in the peripheral venous blood samples of diabetes mellitus (DM) patients compared to normal volunteers, and high-glucose inhibited METTL3 and miR-25-3p expressions in RPE cells. As expected, upregulation of METTL3 and miR-25-3p alleviated the cytotoxic effects of high-glucose on RPE cells, and knockdown of METTL3 and miR-25-3p had opposite effects. Additionally, METTL3 overexpression increased miR-25-3p levels in RPE cells in a microprocessor protein DGCR8-dependent manner, and miR-25-3p ablation abrogated the effects of overexpressed METTL3 on cell functions in high-glucose treated RPE cells. Furthermore, PTEN could be negatively regulated by miR-25-3p, and overexpression of METTL3 increased phosphorylated Akt (p-Akt) levels by targeting miR-25-3p/PTEN axis. Consistently, upregulation of PTEN abrogated the protective effects of METTL3 overexpression on RPE cells treated with high-glucose. Collectively, METTL3 rescued cell viability in highglucose treated RPE cells by targeting miR-25-3p/PTEN/Akt signaling cascade.

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“…Chondrocytes was cultured in complete DMEM supplemented with 15% fetal bovine serum(FBS), 100 units/ml penicillin and 100 µg/ml streptomycin. Chondrocytes were exposed from normal glucose concentration(5.5 mM) to high glucose concentration(10-30 mM) for 3, 6, 12 or 24h [19] . In order to investigate the role of PPARγ in the hyperglycemia-induced deleterious effect on chondrocytes, chondrocytes (> 85% con uent) were incubated in high glucose medium in the presence or absence of PPARγ agonist pioglitazone(50 µM).…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

“…Equal protein (40 µg) was seperated on a 10% SDS gel and transferred into an immobilon-P (PVDF) membrane (Millipore). Western blotting was performed as described previously [19] . Densitometric analysis of the scanned bands was performed using Image J (MD, USA) according to the manufacturer's instructions.…”

Section: Western Blottingmentioning

confidence: 99%

The Role of PPARγ in Hyperglycemia-induced Deleterious Effect on Chondrocytes

Ma¹,

Yang²,

Tan³

et al. 2020

Preprint

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Aims: There is a well-established link between OA and diabetes, and study have shown that hyperglycemia might play an important role in the occurrence and development of OA. Accumulative evidence suggested that PPARγ was involved in AGEs-related disease, including diabetes and OA. The study was designed to investigate the effects of hyperglycemia on the expression of PPARγ in chondrocytes and whether PPARγ agonist pioglitazone had a chondroprotective effect.Main methods: Primary human chondrocytes were incubated with different concentration of glucose medium(5.5mM-30mM) in the presence or absence of PPARγ agonist pioglitazone. The AGEs formation level in chondrocytes culture medium was detected by AGEs specific ELISA kits. The expression of IL-1, MMP-13, TNF-α, PPARγ was determined by western blotting and real-time PCR.Key findings: The AGEs fomation level was time-dependently and dose-dependently increased in chondrocyte culture media. Hyperglycemia could enhance the expression of IL-1β, TNF-α, MMP-13, but the level of PPARγ was decreased in a time-dependent and dose-dependent manner, which was inhibited by PPARγ agonist pioglitazone. Noteworthy, the maximum effect was found to at 20mM glucose medium for 24h.Significance: Hyperglycemia could increase the AGEs formation level and induce inflammatory response and matrix degradation reaction in chondrocytes. PPARγ agonists pioglitazone had a chondroprotective effect via inhibit inflammatory response and matrix degradation reaction. PPARγ could be a potential target for pharmacologic intervention in the treatment of diabetic-induced OA.

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High glucose-induced phospholipase D activity in retinal pigment epithelium cells: New insights into the molecular mechanisms of diabetic retinopathy

Cited by 29 publications

References 65 publications

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/Akt signaling cascade through DGCR8

The Role of PPARγ in Hyperglycemia-induced Deleterious Effect on Chondrocytes

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High glucose-induced phospholipase D activity in retinal pigment epithelium cells: New insights into the molecular mechanisms of diabetic retinopathy

Cited by 29 publications

References 65 publications

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/Akt signaling cascade through DGCR8

The Role of PPARγ&nbsp;in Hyperglycemia-induced Deleterious Effect on Chondrocytes

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The Role of PPARγ in Hyperglycemia-induced Deleterious Effect on Chondrocytes