Blockade of sodium-glucose cotransporter 2 suppresses high glucose-induced angiotensinogen augmentation in renal proximal tubular cells
| Autor: | Michael W. Cypress, Ryousuke Satou, Courtney M Dugas, L. Gabriel Navar, Akemi Katsurada, T. Cooper Woods, Vivian Fonseca |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_specialty Physiology Angiotensinogen Cell Line Kidney Tubules Proximal Renin-Angiotensin System Mice Sodium-Glucose Transporter 2 Internal medicine Diabetes mellitus parasitic diseases medicine Animals Canagliflozin Sodium-Glucose Transporter 2 Inhibitors business.industry Epithelial Cells medicine.disease Angiotensin II Blockade Glucose Endocrinology Sodium/Glucose Cotransporter 2 High glucose Reactive Oxygen Species business Research Article |
| Zdroj: | Am J Physiol Renal Physiol |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00402.2019 |
| Popis: | Renal proximal tubular angiotensinogen (AGT) is increased by hyperglycemia (HG) in diabetes mellitus, which augments intrarenal angiotensin II formation, contributing to the development of hypertension and kidney injury. Sodium-glucose cotransporter 2 (SGLT2) is abundantly expressed in proximal tubular cells (PTCs). The present study investigated the effects of canagliflozin (CANA), a SGLT2 inhibitor, on HG-induced AGT elevation in cultured PTCs. Mouse PTCs were treated with 5–25 mM glucose. CANA (0–10 µM) was applied 1 h before glucose treatment. Glucose (10 mM) increased AGT mRNA and protein levels at 12 h (3.06 ± 0.48-fold in protein), and 1 and 10 µM CANA as well as SGLT2 shRNA attenuated the AGT augmentation. CANA did not suppress the elevated AGT levels induced by 25 mM glucose. Increased AGT expression induced by treatment with pyruvate, a glucose metabolite that does not require SGLT2 for uptake, was not attenuated by CANA. In HG-treated PTCs, intracellular reactive oxygen species levels were elevated compared with baseline (4.24 ± 0.23-fold), and these were also inhibited by CANA. Furthermore, tempol, an antioxidant, attenuated AGT upregulation in HG-treated PTCs. HG-induced AGT upregulation was not inhibited by an angiotensin II receptor antagonist, indicating that HG stimulates AGT expression in an angiotensin II-independent manner. These results indicate that enhanced glucose entry via SGLT2 into PTCs elevates intracellular reactive oxygen species generation by stimulation of glycolysis and consequent AGT augmentation. SGLT2 blockade limits HG-induced AGT stimulation, thus reducing the development of kidney injury in diabetes mellitus. |
| Databáze: | OpenAIRE |
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