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Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy

Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium–glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by...

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Autores principales: Lv, Xin, Wang, Jian, Zhang, Li, Shao, Xian, Lin, Yao, Liu, Hongyan, Ma, Guangyang, Li, Jing, Zhou, Saijun, Yu, Pei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9751039/
https://www.ncbi.nlm.nih.gov/pubmed/36531996
http://dx.doi.org/10.3389/fimmu.2022.993869
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author Lv, Xin
Wang, Jian
Zhang, Li
Shao, Xian
Lin, Yao
Liu, Hongyan
Ma, Guangyang
Li, Jing
Zhou, Saijun
Yu, Pei
author_facet Lv, Xin
Wang, Jian
Zhang, Li
Shao, Xian
Lin, Yao
Liu, Hongyan
Ma, Guangyang
Li, Jing
Zhou, Saijun
Yu, Pei
author_sort Lv, Xin
collection PubMed
description Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium–glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by which the SGLT2 inhibitor canagliflozin attenuates podocyte injury by reversing the imbalance in Helper T cell 1 (Th1)/Helper T cell 2 (Th2) in peripheral blood of rats with membranous nephropathy (MN). MN rats were gavaged with canagliflozin (10 mg/kg/d) and losartan (10 mg/kg/d), respectively, for eight weeks. Compared with the MN group, the urinary ratio of total protein and the creatinine levels of the canagliflozin group decreased significantly. Canagliflozin improved the glomerulus pathological damage, increased the expression levels of podocyte marker proteins. The protective effect of canagliflozin on kidneys was more obvious than that of losartan. Treatment with canagliflozin increased the proportion of Th1 cells by 2.3 times, decreased the proportion of Th2 cells by 68.5%, and significantly restrained the synthesis of immunoglobulin G1 in B-cells and glomerulus subepithelial immune complex deposition. Co-culture of B-cells derived from MN rats with podocytes triggered the activation of phosphorylation of mTOR and ULK1 of podocytes, inhibited podocyte autophagy and resulted in podocyte injury. B-cells derived from canagliflozin treatment rats reversed these effects above. In conclusion, canagliflozin exerts a protective effect on kidneys by reversing the imbalance in Th1/Th2 cells in MN rats and restoring the autophagy of podocytes inhibited by the abnormal immunoglobulin G secretion from B-cells.
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spelling pubmed-97510392022-12-16 Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy Lv, Xin Wang, Jian Zhang, Li Shao, Xian Lin, Yao Liu, Hongyan Ma, Guangyang Li, Jing Zhou, Saijun Yu, Pei Front Immunol Immunology Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium–glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by which the SGLT2 inhibitor canagliflozin attenuates podocyte injury by reversing the imbalance in Helper T cell 1 (Th1)/Helper T cell 2 (Th2) in peripheral blood of rats with membranous nephropathy (MN). MN rats were gavaged with canagliflozin (10 mg/kg/d) and losartan (10 mg/kg/d), respectively, for eight weeks. Compared with the MN group, the urinary ratio of total protein and the creatinine levels of the canagliflozin group decreased significantly. Canagliflozin improved the glomerulus pathological damage, increased the expression levels of podocyte marker proteins. The protective effect of canagliflozin on kidneys was more obvious than that of losartan. Treatment with canagliflozin increased the proportion of Th1 cells by 2.3 times, decreased the proportion of Th2 cells by 68.5%, and significantly restrained the synthesis of immunoglobulin G1 in B-cells and glomerulus subepithelial immune complex deposition. Co-culture of B-cells derived from MN rats with podocytes triggered the activation of phosphorylation of mTOR and ULK1 of podocytes, inhibited podocyte autophagy and resulted in podocyte injury. B-cells derived from canagliflozin treatment rats reversed these effects above. In conclusion, canagliflozin exerts a protective effect on kidneys by reversing the imbalance in Th1/Th2 cells in MN rats and restoring the autophagy of podocytes inhibited by the abnormal immunoglobulin G secretion from B-cells. Frontiers Media S.A. 2022-12-01 /pmc/articles/PMC9751039/ /pubmed/36531996 http://dx.doi.org/10.3389/fimmu.2022.993869 Text en Copyright © 2022 Lv, Wang, Zhang, Shao, Lin, Liu, Ma, Li, Zhou and Yu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lv, Xin
Wang, Jian
Zhang, Li
Shao, Xian
Lin, Yao
Liu, Hongyan
Ma, Guangyang
Li, Jing
Zhou, Saijun
Yu, Pei
Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title_full Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title_fullStr Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title_full_unstemmed Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title_short Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
title_sort canagliflozin reverses th1/th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9751039/
https://www.ncbi.nlm.nih.gov/pubmed/36531996
http://dx.doi.org/10.3389/fimmu.2022.993869
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