Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes

Abstract Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insu...

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Autores principales:	Akira Mima, Toshinori Yasuzawa, Tomomi Nakamura, Shigeru Ueshima
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf35ec76020743edad0e0c0bda670a8f
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spelling	oai:doaj.org-article:cf35ec76020743edad0e0c0bda670a8f2021-12-02T18:18:07ZLinagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes10.1038/s41598-020-62579-72045-2322https://doaj.org/article/cf35ec76020743edad0e0c0bda670a8f2020-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-62579-7https://doaj.org/toc/2045-2322Abstract Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.Akira MimaToshinori YasuzawaTomomi NakamuraShigeru UeshimaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Akira Mima Toshinori Yasuzawa Tomomi Nakamura Shigeru Ueshima Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
description	Abstract Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.
format	article
author	Akira Mima Toshinori Yasuzawa Tomomi Nakamura Shigeru Ueshima
author_facet	Akira Mima Toshinori Yasuzawa Tomomi Nakamura Shigeru Ueshima
author_sort	Akira Mima
title	Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
title_short	Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
title_full	Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
title_fullStr	Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
title_full_unstemmed	Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes
title_sort	linagliptin affects irs1/akt signaling and prevents high glucose-induced apoptosis in podocytes
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/cf35ec76020743edad0e0c0bda670a8f
work_keys_str_mv	AT akiramima linagliptinaffectsirs1aktsignalingandpreventshighglucoseinducedapoptosisinpodocytes AT toshinoriyasuzawa linagliptinaffectsirs1aktsignalingandpreventshighglucoseinducedapoptosisinpodocytes AT tomominakamura linagliptinaffectsirs1aktsignalingandpreventshighglucoseinducedapoptosisinpodocytes AT shigeruueshima linagliptinaffectsirs1aktsignalingandpreventshighglucoseinducedapoptosisinpodocytes
_version_	1718378300174237696

Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes

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