ArticleInternational urology and nephrology2020
A unifying model of glucotoxicity in human renal proximal tubular epithelial cells and the effect of the SGLT2 inhibitor dapagliflozin.
Article in International urology and nephrology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 38 citations in OpenAlex.
- Article
- The impact of SGLT2 inhibitors on uric acid levels in patients with heart failure with preserved ejection fraction: integration of mechanisms and clinical evidence.Frontiers in cardiovascular medicine · 2026Article
- Regulatory networks of post-translational modifications in diabetic kidney disease: from pathogenic mechanisms to therapeutic frontiers.Frontiers in endocrinology · 2026Review
- Overload of Glucose Metabolism as Initiating Factor in Diabetic Embryopathy and Prevention by Glyoxalase 1 Inducer Dietary Supplement.Antioxidants (Basel, Switzerland) · 2025Article
- Understanding and targeting senescence in kidney disease.Clinical kidney journal · 2025Review
- Identification of novel phenotypes in pediatric sepsis based on blood glucose trajectories.Frontiers in pediatrics · 2025Article
- Inhibition of Caspase-3/GSDME Pathway-Mediated Pyroptosis of Renal Tubular Epithelial Cells by Dagliflozin in the Pathogenesis of Diabetic Kidney Disease and Study of Its Mechanism.Diabetes, metabolic syndrome and obesity : targets and therapy · 2025Article
- Molecular Insight into Obesity-Associated Nephropathy: Clinical Implications and Possible Strategies for its Management.Current drug targets · 2025Review
- Targeting oxidative stress in diabetic retinopathy: mechanisms, pathology, and novel treatment approaches.Frontiers in immunology · 2025Review
- Handling the sugar rush: the role of the renal proximal tubule.American journal of physiology. Renal physiology · 2024Review
- Bioinformatic analyses reveal lysosomal-associated protein transmembrane 5 as a potential therapeutic target in lipotoxicity-induced injury in diabetic kidney disease.Renal failure · 2024Article
- Safety and Efficacy of Sodium-Glucose Transport Protein 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Diabetic Kidney Transplant Recipients: Synthesis of Evidence.Journal of clinical medicine · 2024Review
- mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes.International journal of molecular sciences · 2024Review
- Pathomechanisms of Diabetic Kidney Disease.Journal of clinical medicine · 2023Review
- Therapeutic Advances in Diabetic Kidney Disease.International journal of molecular sciences · 2023Review
- SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease.Biomedicines · 2023Review
- Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives.Frontiers in endocrinology · 2023Review
- Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.Frontiers in endocrinology · 2023Article
- Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells.International journal of molecular sciences · 2022Article
- Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGlucotoxicity in renal tubular epithelial cells (RPTECs) contributes to the pathogenesis of diabetic nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may exert their renoprotective effect by preventing glucotoxicity. We tested whether the confirmed in capillary endothelial cells unifying model of glucotoxicity can be applied in RPTECs and the impact of dapagliflozin.
methodsIn primary human RPTECs cultured in normal or high glucose medium in the presence or not of dapagliflozin, we assessed glucose consumption, SCLT2 expression, reactive oxygen species (ROS) production, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity, D-sorbitol and methylglyoxal cell content, O-linked β-N-acetyl glucosamine (O-Glc-NAc)-modified proteins, protein kinase C (PKC) activity, transforming growth factor-β1 (TGF-β1), interleukin-8 (IL-8), cell necrosis, and cell apoptosis using colorimetric and immunoenzymatic assays, and western blotting.
resultsHigh glucose increases SGLT2 expression and glucose consumption. ROS are overproduced, and GAPDH is inhibited. The accumulation due to GAPDH inhibition glycolytic products are diverted into four noxious pathways. The polyol pathway assessed by D-sorbitol, the hexosamine pathway determined by O-GlcNAc-modified proteins, the lipid synthesis pathway assessed by PKC activity, and the advanced glycation end-products (AGEs) formation assessed by methylglyoxal. Eventually, these paths lead to overproduction of TGF-β1 and IL-8, as well as to cell necrosis and apoptosis. Dapagliflozin ameliorates all the above cascade of events.
conclusionsOur results support a unifying model for glucotoxicity in RPTECs. Dapagliflozin by decreasing the elevated glucose influx into the RPTECs under high glucose conditions ameliorates glucotoxicity.
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