ArticleScience translational medicine2021
Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 71 citations in OpenAlex.
- Glycation and receptors: coming of AGE in the midst of danger.Nature reviews. Endocrinology · 2026Review
- Blocking AGEs reduces airway epithelial viral susceptibility in diabetes-exacerbated COPD.EMBO molecular medicine · 2026Article
- RAGE phosphorylation by CK2 in human epithelial cell model: Modulation of connexin 43 expression.iScience · 2026Article
- Structural and molecular principles of DAMP biology.Nature structural & molecular biology · 2026Review
- Lycorine ameliorates diabetic nephropathy by targeting RAGE and inhibiting the HMGB1/RAGE/NF-κB signaling axis.Chinese medicine · 2026Article
- Review
- The AGE-RAGE-DIAPH1 Axis in Type 2 Diabetes and Metabolic Dysfunction: From Carbonyl Stress to Diabetic Myocardial and Neuronal Injury.International journal of molecular sciences · 2026Review
- Kidney-Vascular Metabolic Crosstalk: Altered Lipoproteins in CKD.Circulation research · 2026Review
- Type 2 Diabetes Promotes the Microglial Pyroptosis by Activating NLRP3 Inflammasome to Impede Remyelination After Spinal Cord Injury.Research (Washington, D.C.) · 2026Article
- Decoding RAGE in diabetes: a pathogenic signaling hub modulated by decoy receptors in diabetic complications.Frontiers in clinical diabetes and healthcare · 2026Review
- Advanced glycation endproducts induce cytokine dysregulation and weaken lung epithelial and endothelial barrier integrity.Tissue barriers · 2026Article
- Advanced glycation end products and RAGE signaling in diabetic cardiomyopathy: distinct mechanisms, human evidence, and translational barriers.Frontiers in cardiovascular medicine · 2026Review
- Carnosol exerts anti-inflammatory effects in pulpitis by inhibiting the RAGE/NF-κB signalling pathway.Scientific reports · 2025Article
- Phlorizin-integrated magnetic pollen micromotors for diabetes complication management.Materials today. Bio · 2025Article
- The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice.International journal of molecular sciences · 2025Article
- RAGE Cytosolic Partner Diaph1 Does Not Play an Essential Role in Diabetic Peripheral Neuropathy Progression.Cells · 2025Article
- RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist.Cell chemical biology · 2025Article
- Resina Draconis Promotes Diabetic Wound Healing by Regulating the AGE-RAGE Pathway to Modulate Macrophage Polarization.Current issues in molecular biology · 2025Article
- Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.Pathophysiology : the official journal of the International Society for Pathophysiology · 2025Review
- Negative cooperativity regulates ligand activation of DIAPH1 and other diaphanous related formins.Communications biology · 2025Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
Abstract
The macro- and microvascular complications of type 1 and 2 diabetes lead to increased disease severity and mortality. The receptor for advanced glycation end products (RAGE) can bind AGEs and multiple proinflammatory ligands that accumulate in diabetic tissues. Preclinical studies indicate that RAGE antagonists have beneficial effects on numerous complications of diabetes. However, these antagonists target the extracellular domains of RAGE, which bind distinct RAGE ligands at diverse sites in the immunoglobulin-like variable domain and two constant domains. The cytoplasmic tail of RAGE (ctRAGE) binds to the formin, Diaphanous-1 (DIAPH1), and this interaction is important for RAGE signaling. To comprehensively capture the breadth of RAGE signaling, we developed small-molecule antagonists of ctRAGE-DIAPH1 interaction, termed RAGE229. We demonstrated that RAGE229 is effective in suppressing RAGE-DIAPH1 binding, Förster resonance energy transfer, and biological activities in cellular assays. Using solution nuclear magnetic resonance spectroscopy, we defined the molecular underpinnings of the interaction of RAGE229 with RAGE. Through in vivo experimentation, we showed that RAGE229 assuaged short- and long-term complications of diabetes in both male and female mice, without lowering blood glucose concentrations. Last, the treatment with RAGE229 reduced plasma concentrations of TNF-α, IL-6, and CCL2/JE-MCP1 in diabetic mice, in parallel with reduced pathological and functional indices of diabetes-like kidney disease. Targeting ctRAGE-DIAPH1 interaction with RAGE229 mitigated diabetic complications in rodents by attenuating inflammatory signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.