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Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin
Based on recent clinical trials using sodium-glucose co-transporter 2 inhibitor (SGLT2i) demonstrating the significant improvement of outcomes of diabetic kidney disease (DKD), the paradigm shift from “glomerulocentric” to “tubule centric” pathophysiology in DKD progression has been highlighted. Sev...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9485043/ https://www.ncbi.nlm.nih.gov/pubmed/36148274 http://dx.doi.org/10.1016/j.heliyon.2022.e10615 |
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author | Uehara-Watanabe, Noriko Okuno-Ozeki, Natsuko Nakamura, Itaru Nakata, Tomohiro Nakai, Kunihiro Yagi-Tomita, Aya Ida, Tomoharu Yamashita, Noriyuki Kamezaki, Michitsugu Kirita, Yuhei Matoba, Satoaki Tamagaki, Keiichi Kusaba, Tetsuro |
author_facet | Uehara-Watanabe, Noriko Okuno-Ozeki, Natsuko Nakamura, Itaru Nakata, Tomohiro Nakai, Kunihiro Yagi-Tomita, Aya Ida, Tomoharu Yamashita, Noriyuki Kamezaki, Michitsugu Kirita, Yuhei Matoba, Satoaki Tamagaki, Keiichi Kusaba, Tetsuro |
author_sort | Uehara-Watanabe, Noriko |
collection | PubMed |
description | Based on recent clinical trials using sodium-glucose co-transporter 2 inhibitor (SGLT2i) demonstrating the significant improvement of outcomes of diabetic kidney disease (DKD), the paradigm shift from “glomerulocentric” to “tubule centric” pathophysiology in DKD progression has been highlighted. Several responsible mechanisms for renoprotective effects by SGLT2i have been proposed recently, but the changes in proximal tubule-specific gene expression by SGLT2i in diabetic mice have not been elucidated. We report the analysis of the proximal tubular-specific pathway, demonstrating the downregulation of oxidative phosphorylation in dapagliflozin-treated db/db mice, a type 2 diabetic model. After 8-week treatment of dapagliflozin for db/db mice having a proximal tubule-specific tdTomato reporter, tdTomato-positive cells were isolated by FACS. Pathway analysis of RNA sequencing of isolated tubular epithelia revealed that oxidative phosphorylation was downregulated in dapagliflozin-treated mice. However, depletion of renal tissue ATP content in db/db mice was ameliorated by dapagliflozin administration. Pimonidazole staining demonstrated renal cortical tissue hypoxia in db/db mice, which was improved by dapagliflozin administration. This study suggests that dapagliflozin can ameliorate the excessive oxygen and ATP consumption, and subsequent tissue hypoxia in the diabetic kidney, which may explain, in part, the responsible mechanisms of the renoprotective effects of dapagliflozin. |
format | Online Article Text |
id | pubmed-9485043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-94850432022-09-21 Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin Uehara-Watanabe, Noriko Okuno-Ozeki, Natsuko Nakamura, Itaru Nakata, Tomohiro Nakai, Kunihiro Yagi-Tomita, Aya Ida, Tomoharu Yamashita, Noriyuki Kamezaki, Michitsugu Kirita, Yuhei Matoba, Satoaki Tamagaki, Keiichi Kusaba, Tetsuro Heliyon Research Article Based on recent clinical trials using sodium-glucose co-transporter 2 inhibitor (SGLT2i) demonstrating the significant improvement of outcomes of diabetic kidney disease (DKD), the paradigm shift from “glomerulocentric” to “tubule centric” pathophysiology in DKD progression has been highlighted. Several responsible mechanisms for renoprotective effects by SGLT2i have been proposed recently, but the changes in proximal tubule-specific gene expression by SGLT2i in diabetic mice have not been elucidated. We report the analysis of the proximal tubular-specific pathway, demonstrating the downregulation of oxidative phosphorylation in dapagliflozin-treated db/db mice, a type 2 diabetic model. After 8-week treatment of dapagliflozin for db/db mice having a proximal tubule-specific tdTomato reporter, tdTomato-positive cells were isolated by FACS. Pathway analysis of RNA sequencing of isolated tubular epithelia revealed that oxidative phosphorylation was downregulated in dapagliflozin-treated mice. However, depletion of renal tissue ATP content in db/db mice was ameliorated by dapagliflozin administration. Pimonidazole staining demonstrated renal cortical tissue hypoxia in db/db mice, which was improved by dapagliflozin administration. This study suggests that dapagliflozin can ameliorate the excessive oxygen and ATP consumption, and subsequent tissue hypoxia in the diabetic kidney, which may explain, in part, the responsible mechanisms of the renoprotective effects of dapagliflozin. Elsevier 2022-09-13 /pmc/articles/PMC9485043/ /pubmed/36148274 http://dx.doi.org/10.1016/j.heliyon.2022.e10615 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Uehara-Watanabe, Noriko Okuno-Ozeki, Natsuko Nakamura, Itaru Nakata, Tomohiro Nakai, Kunihiro Yagi-Tomita, Aya Ida, Tomoharu Yamashita, Noriyuki Kamezaki, Michitsugu Kirita, Yuhei Matoba, Satoaki Tamagaki, Keiichi Kusaba, Tetsuro Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title | Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title_full | Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title_fullStr | Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title_full_unstemmed | Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title_short | Proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
title_sort | proximal tubular epithelia-specific transcriptomics of diabetic mice treated with dapagliflozin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9485043/ https://www.ncbi.nlm.nih.gov/pubmed/36148274 http://dx.doi.org/10.1016/j.heliyon.2022.e10615 |
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