ArticlePloS one2019
The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 2 of them syntheses that pooled it.
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Who cites it
45 citing papers in PubMed, 2 syntheses or guidelines pooled it, 71 citations in OpenAlex.
- SGLT2 inhibitors for delaying diabetic retinopathy: a systematic review and meta-analysis.International ophthalmology · 2025Pooled it
- European Association for the Study of Obesity (EASO) Position Statement on Medical Nutrition Therapy for the Management of Individuals with Overweight or Obesity and Cancer.Obesity facts · 2025Guideline
- Role of NLRP3 Inflammasome Inhibitors in Endothelial Dysfunction and Vascular Repair.Antioxidants (Basel, Switzerland) · 2026Review
- The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.International journal of molecular sciences · 2026Review
- Hydroxycarboxylic acid receptor 2 (GPR109A) and retinopathies: pathways and prospects.Frontiers in medicine · 2026Review
- β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review).International journal of molecular medicine · 2026Review
- BDH1-Dependent Ketone Body Metabolism Maintains Müller Cell Homeostasis and Retinal Function.bioRxiv : the preprint server for biology · 2025Article
- HCAR2 is a novel receptor for heme.Blood advances · 2025Article
- Article
- A ketogenic diet regulates microglial activation to treat drug addiction.Frontiers in pharmacology · 2025Review
- Ketogenic diet and microRNAs: focus on cognitive function.Frontiers in nutrition · 2025Review
- Ketogenic diet and β-hydroxybutyrate in osteoporosis: current progress and controversy.Frontiers in nutrition · 2025Review
- Article
- Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.Journal of clinical medicine · 2024Review
- A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice.Cell communication and signaling : CCS · 2024Article
- Spatial Proteomics Reveals Alcohol-Induced Damages to the Crypts and Villi of the Mouse Small Intestine.Journal of proteome research · 2024Article
- Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review.Biomedical journal · 2024Review
- The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle.American journal of physiology. Cell physiology · 2024Review
- Developing poly(ethylene glycol)-Science and technology of advanced materials · 2024Article
- Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe role of the hydroxycarboxylic acid receptor 2 (HCA2) in the retinal damage induced by diabetes has never been explored. In this context, the present study highlights an upregulation of retinal HCA2 receptors in diabetic C57BL6J mice. Moreover, we illustrate that HCA2 receptors exert an anti-inflammatory effect on the retinal damage induced by diabetes when activated by the endogenous ligand β-hydroxybutyrate. METHODOLOGY: Seven-to-10-week-old C57BL6J mice were rendered diabetic by a single intraperitoneal injection of streptozotocin (75 mg/kg of body weight) and monitored intermittently over a 10-week period extending from the initial diabetes assessment. Mice with a fasting blood glucose level higher than 250 mg/dl for 2 consecutive weeks after streptozotocin injection were treated twice a week with intraperitoneal injections of 25-50-100 mg/kg β-hydroxybutyrate.
resultsInterestingly, while the retinal endoplasmic reticulum stress markers (pPERK, pIRE1, ATF-6α) were elevated in diabetic C57BL6J mice, their levels were significantly reduced by the systemic intraperitoneal treatment with 50 mg/kg and 100 mg/kg β-hydroxybutyrate. These mice also exhibited high NLRP3 inflammasome activity and proinflammatory cytokine levels. In fact, the elevated levels of retinal NLRP3 inflammasome activation markers (NLRP3, ASC, caspase-1) and of the relative proinflammatory cytokines (IL-1β, IL-18) were significantly reduced by 50 mg/kg and 100 mg/kg β-hydroxybutyrate treatment. These doses also reduced the high apoptotic cell number exhibited by the diabetic mice in the retinal outer nuclear layer (ONL) and increased the ONL low connexin 43 expression, leading to an improvement in retinal permeability and homeostasis.
conclusionsThese data suggest that the systemic treatment of diabetic C57BL6J mice with BHB activates retinal HCA2 and inhibits local damage.
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