Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors
| العنوان: | Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors |
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| المؤلفون: | Joseph Tam, Boaz Tirosh, Yael Riahi, Tal Israeli, Ernesto Bernal Mizrachi, Aviram Kogot-Levin, Ofri Mosenzon, Liad Hinden, Gil Leibowitz, Erol Cerasi |
| المصدر: | Cell Reports Cell Reports, Vol 32, Iss 4, Pp 107954-(2020) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, medicine.medical_specialty, complications, Swine, Renal cortex, Renal function, mTORC1, Mechanistic Target of Rapamycin Complex 1, Kidney, General Biochemistry, Genetics and Molecular Biology, Article, Diabetic nephropathy, Kidney Tubules, Proximal, 03 medical and health sciences, Mice, 0302 clinical medicine, Fibrosis, Internal medicine, Diabetes mellitus, medicine, Renal fibrosis, Animals, Humans, Hypoglycemic Agents, Diabetic Nephropathies, lcsh:QH301-705.5, Sodium-Glucose Transporter 2 Inhibitors, diabetes, business.industry, fibrosis, medicine.disease, diabetic kidney disease, 3. Good health, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, lcsh:Biology (General), Diabetes Mellitus, Type 2, mTOR, Kidney Failure, Chronic, biological phenomena, cell phenomena, and immunity, business, 030217 neurology & neurosurgery, signal transduction, SGLT2 inhibitors, Kidney disease |
| الوصف: | Summary Diabetic kidney disease (DKD) increases the risk for mortality and is the leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of DKD, especially in patients with advanced kidney disease. Herein, we show that in diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) along with enhanced tubule-interstitial fibrosis; this is prevented by SGLT2i. Constitutive activation of mTORC1 in RPTCs induces renal fibrosis and failure and abolishes the renal-protective effects of SGLT2i in diabetes. On the contrary, partial inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function. Stimulation of mTORC1 in RPTCs turns on a pro-fibrotic program in the renal cortex, whereas its inhibition in diabetes reverses the alterations in gene expression. We suggest that RPTC mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis. Graphical Abstract Highlights • In diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) • Diabetes and SGLT2i regulate mTORC1 by modulating nutrient transport to RPTCs • Inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function • RPTC mTORC1 mediates renal fibrosis in diabetes and the beneficial effects of SGLT2i Kogot-Levin et al. show that treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of diabetic kidney disease (DKD), which is the leading cause of end-stage renal disease. The nutrient sensor mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis. |
| تدمد: | 2211-1247 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::78512fcfea88b17e203ded1044c55a0e https://pubmed.ncbi.nlm.nih.gov/32726619 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....78512fcfea88b17e203ded1044c55a0e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22111247 |
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