GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease

Wen, Mei; Zhu, Biao; Su, Yi; Liang, Yanhua; He, Mengqi; Luo, Haizhao; Ye, Jingwen

doi:10.1016/j.mce.2021.111422

Cited by 9 publications

(6 citation statements)

References 43 publications

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“…Using western blot, we revealed GDF11 activated both the classical TGF-β/Smad2/3 and non-Smad PI3K-Akt pathways. Numerous studies have demonstrated GDF11 could activate classical TGF-β/Smad (including TGF-β/Smad2/3 and TGF-β/Smad1/5/8) signal pathway to regulate cell behaviors in multiple cell types, such as osteoblasts, human umbilical vein endothelial cells, neural stem cells, mice retinal microvascular endothelial cells, and bone marrow mesenchymal stem cells [ 14 , 20 , 28 , 29 ]. Similarly, GDF11 also activated non-Smad (e.g., AMPK, MAPK, mTOR, PI3K) pathways in a wide range of cell types, such as cardiomyocytes, neural stem cells, human hepatocellular carcinoma cells, primary hepatocytes, and mesenchymal stem cells [ 14 , 30 , 31 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

GDF11 Regulates PC12 Neural Stem Cells via ALK5-Dependent PI3K-Akt Signaling Pathway

Wang

Jiang

Liu

et al. 2022

IJMS

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Growth differentiation factor 11 (GDF11), belonging to the transforming factor-β superfamily, regulates anterior-posterior patterning and inhibits neurogenesis during embryonic development. However, recent studies recognized GDF11 as a rejuvenating (or anti-ageing) factor to reverse age-related cardiac hypertrophy, repair injured skeletal muscle, promote cognitive function, etc. The effects of GDF11 are contradictory and the mechanism of action is still not well clarified. The objective of the present study was to investigate effects of GDF11 on PC12 neural stem cells in vitro and to reveal the underlying mechanism. We systematically assessed the effects of GDF11 on the life activities of PC12 cells. GDF11 significantly suppressed cell proliferation and migration, promoted differentiation and apoptosis, and arrested cell cycle at G2/M phase. Both TMT-based proteomic analysis and phospho-antibody microarray revealed PI3K-Akt pathway was enriched when treated with GDF11. Inhibition of ALK5 or PI3K obviously attenuated the effects of GDF11 on PC12 neural stem cells, which exerted that GDF11 regulated neural stem cells through ALK5-dependent PI3K-Akt signaling pathway. In summary, these results demonstrated GDF11 could be a negative regulator for neurogenesis via ALK5 activating PI3K-Akt pathway when it directly acted on neural stem cells.

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Section: Discussionmentioning

confidence: 99%

GDF11 Regulates PC12 Neural Stem Cells via ALK5-Dependent PI3K-Akt Signaling Pathway

Wang

Jiang

Liu

et al. 2022

IJMS

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“…One molecule of interest is GDF11, a member of the TGF-β superfamily, which has previously been associated with the regulation of retinal neurogenesis and promotion of angiogenic activity in ischemic limb tissue in diabetic rats [ 67 , 68 ]. Mei et al studied the actions of supplemental GDF11 in the retinas of diabetic rats to explore the possibility of halting the progression of DR [ 69 ]. The results of the study showed that the administration of GDF11 was protective against retinal vascular endothelial cell and retinal pericyte apoptosis, two major characteristics of DR.…”

Section: Current Research On Tgf-β’s Potential Role In Dr Treatmentmentioning

confidence: 99%

“…The utility of targeting TGF-β signaling pathways for the treatment of DR has also been demonstrated in vitro using acrolein, an endogenous compound which has been previously implicated in TGF-β-mediated retinal pigment epithelium (RPE) cell death in the setting of diabetes [ 69 , 70 , 71 ]. ARPE cells incubated in glucose and acrolein showed significant cell death [ 71 ].…”

Section: Current Research On Tgf-β’s Potential Role In Dr Treatmentmentioning

confidence: 99%

TGF-β Signaling Pathways in the Development of Diabetic Retinopathy

Callan,

Jha,

Valdez

et al. 2024

IJMS

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Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting a significant portion of the global population, has long been viewed primarily as a microvascular disorder. However, emerging evidence suggests that it should be redefined as a neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family has emerged as a major contributor to DR pathogenesis due to its pivotal role in retinal vascular homeostasis, endothelial cell barrier function, and pericyte differentiation. However, the precise roles of TGF-β signaling in DR remain incompletely understood, with conflicting reports on its impact in different stages of the disease. Additionally, the BMP subfamily within the TGF-β superfamily introduces further complexity, with BMPs exhibiting both pro- and anti-angiogenic properties. Furthermore, TGF-β signaling extends beyond the vascular realm, encompassing immune regulation, neuronal survival, and maintenance. The intricate interactions between TGF-β and reactive oxygen species (ROS), non-coding RNAs, and inflammatory mediators have been implicated in the pathogenesis of DR. This review delves into the complex web of signaling pathways orchestrated by the TGF-β superfamily and their involvement in DR. A comprehensive understanding of these pathways may hold the key to developing targeted therapies to halt or mitigate the progression of DR and its devastating consequences.

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“…Fang and Chang [31] proved the protective role of celastrol in HGinduced in vitro DR cell model by inhibiting the proliferation, invasion and angiogenesis of retinal endothelial cells. It was demonstrated by Mei et al [32] that growth differentiation factor 11 (GDF11) protected against DR by alleviating retinal cell death, inflammatory reaction and blood-retinal barrier breakdown. Consistently, it was uncovered in this study that Api greatly relieved HG-induced HRMECs migration and angiogenesis, elevated vascular permeability and proinflammatory cytokines production, and high ROS generation and oxidative stress, supporting that protective role of Api against DR pathophysiology.…”

Section: Nox4 and P38 Mapk Signaling Involved In The Protectivementioning

confidence: 99%

Role of apigenin in high glucose-induced retinal microvascular endothelial cell dysfunction via regulating NOX4/p38 MAPK pathway in vitro

Liu¹

2023

Int J Ophthalmol

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AIM: To investigate the retinoprotective role of Apigenin (Api) against high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs), and to explore its regulatory mechanism. METHODS: HRMECs were stimulated by HG for 48h to establish the in vitro cell model. Different concentrations of Api (2.5, 5, and 10 μmol/L) were applied for treatment. Cell counting kit-8 (CCK-8), Transwell, and tube formation assays were performed to examine the effects of Api on the viability, migration, and angiogenesis in HG-induced HRMECs. Vascular permeability was evaluated by Evans blue dye. The inflammatory cytokines and oxidative stress-related factors were measured using their commercial kits. Protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and p38 mitogen-activated protein kinase (MAPK) was measured by Western blot. RESULTS: Api prevented HG-induced HRMECs viability, migration, angiogenesis, and vascular permeability in a concentration-dependent manner. Meanwhile, Api also concentration-dependently inhibited inflammation and oxidative stress in HRMECs exposed to HG. In addition, HG caused an elevated expression of NOX4, which was retarded by Api treatment. HG stimulation facilitated the activation of p38 MAPK signaling in HRMECs, and Api could weaken this activation partly via downregulating NOX4 expression. Furthermore, overexpression of NOX4 or activation of p38 MAPK signaling greatly weakened the protective role of Api against HG-stimulated HRMECs. CONCLUSION: Api might exert a beneficial role in HG-stimulated HRMECs through regulating NOX4/p38 MAPK pathway.

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GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease

Cited by 9 publications

References 43 publications

GDF11 Regulates PC12 Neural Stem Cells via ALK5-Dependent PI3K-Akt Signaling Pathway

GDF11 Regulates PC12 Neural Stem Cells via ALK5-Dependent PI3K-Akt Signaling Pathway

TGF-β Signaling Pathways in the Development of Diabetic Retinopathy

Role of apigenin in high glucose-induced retinal microvascular endothelial cell dysfunction via regulating NOX4/p38 MAPK pathway in vitro

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