Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy
| Autor: | So-Young Lee, Sang Hoon Kim, Dong Ho Yang, Jisu Oh, Dong-Jin Kim, Jun Mo Kang, Jae-Hee Kim, Jin Hyung Heo, Seon Hwa Park, Yu Ho Lee, Sang-Ho Lee, Min Ji Sung |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Physiology Gene Expression 030204 cardiovascular system & hematology Pharmacology Mitochondrial fragmentation Cell Line Diabetes Mellitus Experimental Kidney Tubules Proximal Mice 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Glucosides Sodium-Glucose Transporter 2 Tubulopathy Autophagy medicine Empagliflozin Animals Humans Diabetic Nephropathies Benzhydryl Compounds Sodium-Glucose Transporter 2 Inhibitors Organelle Biogenesis Chemistry medicine.disease Adenosine Monophosphate Mitochondria Mice Inbred C57BL 030104 developmental biology Apoptosis Regulatory Proteins Reactive Oxygen Species Cotransporter |
| Zdroj: | American Journal of Physiology-Renal Physiology. 317:F767-F780 |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00565.2018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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