ArticleInternational journal of molecular medicine2015
The MAPK signaling pathway mediates the GPR91-dependent release of VEGF from RGC-5 cells.
Article in International journal of molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Diabetic retinopathy: shaped by the "hidden hand" of post-translational modifications.Molecular neurodegeneration · 2026Review
- Fenofibrate in ophthalmology: therapeutic efficacy and mechanisms.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2026Review
- Growth factor and hypoxia-inducible factor alpha content in the retina of male Wistar rats in experimental diabetic retinopathy and the effect of cellular protein kinase blockade.Frontiers in endocrinology · 2025Article
- Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.Scientific reports · 2024Article
- Mechanistic Understanding of Dexamethasone-Mediated Protection against Remdesivir-Induced Hepatotoxicity.Molecular pharmacology · 2024Article
- Small RNA Sequencing Analysis of STZ-Injured Pancreas Reveals Novel MicroRNA and Transfer RNA-Derived RNA with Biomarker Potential for Diabetes Mellitus.International journal of molecular sciences · 2023Article
- Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes.Medical oncology (Northwood, London, England) · 2023Review
- Review
- The Role of Mitochondrial Enzymes, Succinate-Coupled Signaling Pathways and Mitochondrial Ultrastructure in the Formation of Urgent Adaptation to Acute Hypoxia in the Myocardium.International journal of molecular sciences · 2022Article
- Succinate as a New Actor in Pluripotency and Early Development?Metabolites · 2022Review
- Article
- Sirt5-mediated desuccinylation of OPTN protects retinal ganglion cells from autophagic flux blockade in diabetic retinopathy.Cell death discovery · 2022Article
- Dietary succinate supplementation to maternal mice improves fetal brown adipose tissue development and thermogenesis of female offspring.The Journal of nutritional biochemistry · 2022Article
- Advances in Mechanism Research onFrontiers in pharmacology · 2022Review
- SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes.International journal of molecular sciences · 2021Article
- Key regulatory genes and signaling pathways involved in islet culture: a bioinformatic analysis.International journal of clinical and experimental pathology · 2021Article
- Bone Morphogenetic Protein-2 Induces Non-Canonical Inflammatory and Oxidative Pathways in Human Retinal Endothelial Cells.Frontiers in immunology · 2020Article
- Polygonatum sibiricum polysaccharide potentially attenuates diabetic retinal injury in a diabetic rat model.Journal of diabetes investigation · 2019Article
- Receptors of intermediates of carbohydrate metabolism, GPR91 and GPR99, mediate axon growth.PLoS biology · 2018Article
- Succinate promotes stem cell migration through the GPR91-dependent regulation of DRP1-mediated mitochondrial fission.Scientific reports · 2017Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Vascular endothelial growth factor (VEGF) is one of the major regulatory molecules in diabetic retinopathy (DR). In our previous study, we demonstrated that succinate levels were elevated in the retinas of diabetic rats and that the knockdown of the succinate receptor, G-protein-coupled receptor 91 (GPR91), inhibited the release of VEGF and attenuated retinal vascular disorder in the early stages of DR. In the present study, we examined the signaling pathways involved in the GPR91-dependent release of VEGF in the retinal ganglion cell line, RGC-5. The cells were infected with a lentiviral small hairpin RNA (shRNA) expression vector targeting GPR91 (LV.shGPR91). Immunofluorescence staining revealed that GPR91 was predominantly localized in the cell bodies of the RGC-5 cells. RT-qPCR, western blot analysis and ELISA indicated that succinate exposure upregulated VEGF expression, activated the extracellular signal-regulated protein kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways and led to the release of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). The knockdown of GPR91 inhibited ERK1/2 and JNK activity, but did not inhibit the activation of the p38 MAPK pathway. The increase in COX-2 expression and the release of PGE2 were inhibited by transduction with LV.shGPR91 and ERK1/2, JNK and COX-2 inhibitors. The expression and release of VEGF showed similar results. Cell Counting Kit-8 (CCK-8) assays revealed that the shRNA-mediated knockdown of GPR91 decreased the proliferation of RF/6A cells cultured in succinate-conditioned medium. Our data suggest that GPR91 modulates the succinate-induced release of VEGF through the MAPK/COX-2/PGE2 signaling pathway.
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