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SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway

Loss of podocyte is a characteristic pathological change of diabetic nephropathy (DN) which is associated with increased proteinuria. Many studies have shown that novel inhibitors of sodium–glucose cotransporter 2 (SGLT2-is), such as dapagliflozin, exert nephroprotective effect on delaying DN progre...

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Autores principales: Guo, Ruixue, Wang, Peipei, Zheng, Xuejun, Cui, Wen, Shang, Jin, Zhao, Zhanzheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550168/
https://www.ncbi.nlm.nih.gov/pubmed/36225569
http://dx.doi.org/10.3389/fphar.2022.897167
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author Guo, Ruixue
Wang, Peipei
Zheng, Xuejun
Cui, Wen
Shang, Jin
Zhao, Zhanzheng
author_facet Guo, Ruixue
Wang, Peipei
Zheng, Xuejun
Cui, Wen
Shang, Jin
Zhao, Zhanzheng
author_sort Guo, Ruixue
collection PubMed
description Loss of podocyte is a characteristic pathological change of diabetic nephropathy (DN) which is associated with increased proteinuria. Many studies have shown that novel inhibitors of sodium–glucose cotransporter 2 (SGLT2-is), such as dapagliflozin, exert nephroprotective effect on delaying DN progression. However, the mechanisms underlying SGLT2-associated podocyte injury are still not fully elucidated. Here, we generated streptozotocin-induced DN models and treated them with dapagliflozin to explore the possible mechanisms underlying SGLT2 regulation. Compared to mice with DN, dapagliflozin-treated mice exhibited remission of pathological lesions, including glomerular sclerosis, thickening of the glomerular basement membrane (GBM), podocyte injury in the glomeruli, and decreased nephrotoxin levels accompanied by decreased SGLT2 expression. The mRNA expression profiles of these treated mice revealed the significance of the insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. KEGG analysis confirmed that the phosphatidylinositol signaling system and insulin signaling pathway were enriched. Western blotting showed that SGLT2-is inhibited the increase of mesenchymal markers (α-SMA, SNAI-1, and ZEB2) and the loss of podocyte markers (nephrin and E-cad). Additionally, SGLT2, IGF1R, phosphorylated PI3K, α-SMA, SNAI-1, and ZEB2 protein levels were increased in high glucose-stimulated human podocytes (HPC) and significantly decreased in dapagliflozin-treated (50 nM and 100 nM) or OSI-906-treated (inhibitor of IGF1R, 60 nM) groups. However, the use of both inhibitors did not enhance this protective effect. Next, we analyzed urine and plasma samples from a cohort consisting of 13 healthy people and 19 DN patients who were administered with (n = 9) or without (n = 10) SGLT2 inhibitors. ELISA results showed decreased circulating levels of IGF1 and IGF2 in SGLT2-is-treated DN patients compared with DN patients. Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte epithelial–mesenchymal transition (EMT). Modulating IGF1R expression may be a novel approach for DN therapy.
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spelling pubmed-95501682022-10-11 SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway Guo, Ruixue Wang, Peipei Zheng, Xuejun Cui, Wen Shang, Jin Zhao, Zhanzheng Front Pharmacol Pharmacology Loss of podocyte is a characteristic pathological change of diabetic nephropathy (DN) which is associated with increased proteinuria. Many studies have shown that novel inhibitors of sodium–glucose cotransporter 2 (SGLT2-is), such as dapagliflozin, exert nephroprotective effect on delaying DN progression. However, the mechanisms underlying SGLT2-associated podocyte injury are still not fully elucidated. Here, we generated streptozotocin-induced DN models and treated them with dapagliflozin to explore the possible mechanisms underlying SGLT2 regulation. Compared to mice with DN, dapagliflozin-treated mice exhibited remission of pathological lesions, including glomerular sclerosis, thickening of the glomerular basement membrane (GBM), podocyte injury in the glomeruli, and decreased nephrotoxin levels accompanied by decreased SGLT2 expression. The mRNA expression profiles of these treated mice revealed the significance of the insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. KEGG analysis confirmed that the phosphatidylinositol signaling system and insulin signaling pathway were enriched. Western blotting showed that SGLT2-is inhibited the increase of mesenchymal markers (α-SMA, SNAI-1, and ZEB2) and the loss of podocyte markers (nephrin and E-cad). Additionally, SGLT2, IGF1R, phosphorylated PI3K, α-SMA, SNAI-1, and ZEB2 protein levels were increased in high glucose-stimulated human podocytes (HPC) and significantly decreased in dapagliflozin-treated (50 nM and 100 nM) or OSI-906-treated (inhibitor of IGF1R, 60 nM) groups. However, the use of both inhibitors did not enhance this protective effect. Next, we analyzed urine and plasma samples from a cohort consisting of 13 healthy people and 19 DN patients who were administered with (n = 9) or without (n = 10) SGLT2 inhibitors. ELISA results showed decreased circulating levels of IGF1 and IGF2 in SGLT2-is-treated DN patients compared with DN patients. Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte epithelial–mesenchymal transition (EMT). Modulating IGF1R expression may be a novel approach for DN therapy. Frontiers Media S.A. 2022-09-26 /pmc/articles/PMC9550168/ /pubmed/36225569 http://dx.doi.org/10.3389/fphar.2022.897167 Text en Copyright © 2022 Guo, Wang, Zheng, Cui, Shang and Zhao. 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 Pharmacology
Guo, Ruixue
Wang, Peipei
Zheng, Xuejun
Cui, Wen
Shang, Jin
Zhao, Zhanzheng
SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title_full SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title_fullStr SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title_full_unstemmed SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title_short SGLT2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway
title_sort sglt2 inhibitors suppress epithelial–mesenchymal transition in podocytes under diabetic conditions via downregulating the igf1r/pi3k pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550168/
https://www.ncbi.nlm.nih.gov/pubmed/36225569
http://dx.doi.org/10.3389/fphar.2022.897167
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