Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy
2019
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- Autor(en) / Beteiligte
- Titel
- Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy
- Ist Teil von
- American journal of physiology. Renal physiology, 2019-10, Vol.317 (4), p.F767-F780
- Ort / Verlag
- United States: American Physiological Society
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- We examined the effects of empagliflozin, a selective inhibitor of Na -glucose cotransporter 2, on mitochondrial quality control and autophagy in renal tubular cells in a diabetic environment in vivo and in vitro. Human renal proximal tubular cells (hRPTCs) were incubated under high-glucose conditions. Diabetes was induced with streptozotocin in male C57BL/6J mice. Improvements in mitochondrial biogenesis and balanced fusion-fission protein expression were noted in hRPTCs after treatment with empagliflozin in high-glucose media. Empagliflozin also increased autophagic activities in renal tubular cells in the high-glucose environment, which was accompanied with mammalian target of rapamycin inhibition. Moreover, reduced mitochondrial reactive oxygen species production and decreased apoptotic and fibrotic protein expression were observed in hRPTCs after treatment with empagliflozin, even in the hyperglycemic circumstance. Importantly, empagliflozin restored AMP-activated protein kinase-α phosphorylation and normalized levels of AMP-to-ATP ratios in hRPTCs subjected to a high-glucose environment, which suggests the way that empagliflozin is involved in mitochondrial quality control. Empagliflozin effectively suppressed Na -glucose cotransporter 2 expression and ameliorated renal morphological changes in the kidneys of streptozotocin-induced diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased and 8-hydroxy-2'-deoxyguanosine content was low in renal tubular cells of empagliflozin treatment groups compared with those of the diabetic control group. We suggest one mechanism related to the renoprotective actions of empagliflozin, which reverse mitochondrial dynamics and autophagy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1931-857XeISSN: 1522-1466DOI: 10.1152/ajprenal.00565.2018Titel-ID: cdi_proquest_miscellaneous_2270004682
- Format
- –
- Schlagworte
- Adenosine Monophosphate - metabolism, Adenosine Triphosphate - metabolism, AMP, AMP-activated protein kinase, Animals, Apoptosis, Apoptosis Regulatory Proteins - antagonists & inhibitors, Autophagy, Autophagy - drug effects, Benzhydryl Compounds - therapeutic use, Cell Line, Clear cell-type renal cell carcinoma, Deoxyguanosine, Diabetes, Diabetes mellitus, Diabetes Mellitus, Experimental - drug therapy, Diabetes Mellitus, Experimental - genetics, Diabetes Mellitus, Experimental - pathology, Diabetic Nephropathies - drug therapy, Diabetic Nephropathies - pathology, Electron microscopy, Fusion protein, Gene Expression - drug effects, Glucose, Glucosides - therapeutic use, Humans, Kidney Tubules, Proximal - drug effects, Kidney Tubules, Proximal - pathology, Kidneys, Kinases, Male, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondria - drug effects, Mitochondria - pathology, Organelle Biogenesis, Phagocytosis, Phosphorylation, Protein expression, Proteins, Quality control, Rapamycin, Reactive oxygen species, Reactive Oxygen Species - metabolism, Sodium-Glucose Transporter 2 - metabolism, Sodium-Glucose Transporter 2 Inhibitors - therapeutic use, Streptozocin, TOR protein