GLP-1 Treatment Improves Diabetic Retinopathy by Alleviating Autophagy through GLP-1R-ERK1/2-HDAC6 Signaling Pathway

Cai, Xiangsheng; Li, Jingjing; Wang, Mingzhu; She, Miaoqin; Tang, Yun; Li, Jinlong; Li, Hongwei; Hui, Hongxiang

doi:10.7150/ijms.20962

Cited by 61 publications

(46 citation statements)

References 32 publications

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“…The results indicated that exendin-4 pretreatment attenuated the hIAPP-induced increase in the LC3II/I ratio and decrease in p62 expression, both of which are indicators of autophagy. Previous studies have demonstrated that GLP-1 exerts protective effects by inhibiting excessive autophagy (10,34,35). All of these studies, taken together with the present results, suggest that exendin-4 may exhibit protective effects by attenuating hIAPP-induced autophagy in MIN6 cells.…”

Section: Discussionsupporting

confidence: 83%

A GLP‑1 receptor agonist attenuates human islet amyloid polypeptide‑induced autophagy and apoptosis in MIN6 cells

et al. 2018

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Type 2 diabetes mellitus (T2DM) is characterized by the dysfunction and loss of pancreatic islet β-cells, in part due to islet amyloid deposits derived from islet amyloid polypeptide (IAPP). The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 enhances the insulin secretory response by increasing β-cell mass in T2DM. However, it is unknown whether exendin-4 protects β-cells from IAPP-mediated autophagy and apoptosis. In the present study, reverse transcription-quantitative polymerase chain reaction, ELISA and western blotting were used to detected the mRNA and protein expression of insulin/hIAPP and other signaling molecules, while the mechanisms underlying these effects were also determined. Exendin-4 increased the level of insulin secretion, which was greater than that of IAPP, leading to a beneficial IAPP/insulin secretion pattern. In MIN6 cells incubated with 25 mM glucose, exendin-4 decreased the ratio of light chain 3 (LC3)-II/I, which was accompanied by an increase in p62 protein. In a hIAPP-overexpressing MIN6 cell model, exendin-4 prevented the hIAPP-induced increase in the LC3II/I ratio and decrease in p62 expression. In addition, exendin-4 pretreatment reduced hIAPP-induced activation of cleaved caspase-3, suggesting that exendin-4 may protect MIN6 cells against apoptosis. Taken together, the results highlight hIAPP as a critical mediator of β-cell loss and suggest that the GLP-1 receptor agonist exendin-4 may be a potential therapeutic agent for hIAPP-induced β-cell damage.

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Section: Discussionsupporting

confidence: 83%

A GLP‑1 receptor agonist attenuates human islet amyloid polypeptide‑induced autophagy and apoptosis in MIN6 cells

et al. 2018

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“…In this study, we investigated the role of the histone deacetylase HDAC6 in the early events characterizing the progression of an experimental model of DR. Dysregulation of the processes of acetylation/deacetylation of nuclear and cellular proteins has been shown to be associated with different pathologic conditions including diabetes [12][13][14][15][16][17][18]23]. Previous findings linked the activity of several histone deacetylases to the pathogenesis of DR [23,24]. A specific contribution of HDAC1, 2, and 8 to global acetylation of retinal histones in the diabetic retina was found to be involved not only to progression of DR but also to the metabolic memory phenomenon [23].…”

Section: Discussionmentioning

confidence: 93%

“…While the specific role of HDAC6 in the diabetic retina has not been studied before, HDAC6 inhibition has been shown to alleviate myocardial ischemia-reperfusion injury in diabetic rats [16] and to ameliorate diabetic kidney disease [15], predominantly through antioxidant effects. Interestingly, in the diabetic retina, downregulation of HDAC6 was linked to the effects of exogenous GLP-1 in alleviating oxidative stress-induced apoptosis and autophagy of retinal cells [24].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

et al. 2020

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We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a rat model of type 1 diabetes, were used as model of DR. HDAC6 expression and activity were increased in human diabetic postmortem donors and STZ-rat retinas and were augmented in HuREC exposed to glucidic stress (25 mM glucose). Administration of the HDAC6 specific inhibitor Tubastatin A (TS) (10 mg/kg) prevented retinal microvascular hyperpermeability and up-regulation of inflammatory markers. Furthermore, in STZ-rats, TS decreased the levels of senescence markers and rescued the expression and activity of the histone deacetylase sirtuin 1 (SIRT1), while downregulating the levels of free radicals and of the redox stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). The antioxidant effects of TS, consequent to HDAC6 inhibition, were associated with preservation of Nrf2-dependent gene expression and up-regulation of thioredoxin-1 activity. In vitro data, obtained from HuREC, exposed to glucidic stress, largely replicated the in vivo results further confirming the antioxidant effects of HDAC6 inhibition by TS in the diabetic rat retina. In summary, our data implicate HDAC6 activation in mediating hyperglycemia-induced retinal oxidative/nitrative stress leading to retinal microangiopathy and, potentially, DR.

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“…And the administration of liraglutide ameliorated metabolic disturbance by regulating autophagy to a large extent. GLP-1 is thought to exert its functions through GLP-1R (Cai et al, 2017). To explore the receptor-dependent mechanism of liraglutide on erectile function, we examined the expression profiles of GLP-1R by immunohistochemistry in the corpus cavernosum of all groups.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus

Yuan

Gao

et al. 2020

Front. Pharmacol.

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Background: Erectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro. Methods: Type 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins. Results: Administration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor. Conclusion: Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose

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GLP-1 Treatment Improves Diabetic Retinopathy by Alleviating Autophagy through GLP-1R-ERK1/2-HDAC6 Signaling Pathway

Cited by 61 publications

References 32 publications

A GLP‑1 receptor agonist attenuates human islet amyloid polypeptide‑induced autophagy and apoptosis in MIN6 cells

A GLP‑1 receptor agonist attenuates human islet amyloid polypeptide‑induced autophagy and apoptosis in MIN6 cells

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus

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