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The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease
Introduction: Profibrotic phenotype of renal tubular epithelial cells (TECs) featured with epithelial to mesenchymal transition (EMT) and profibrotic factors secretion, and aberrant accumulation of CD206( + ) M2 macrophages are the key points in the transition from acute kidney injury (AKI) to chron...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285316/ https://www.ncbi.nlm.nih.gov/pubmed/37361201 http://dx.doi.org/10.3389/fphar.2023.1169054 |
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author | Shu, Huapan Wang, Yumei Zhang, Hui Dong, Qingqing Sun, Lulu Tu, Yuchi Liao, Qianqian Feng, Li Yao, Lijun |
author_facet | Shu, Huapan Wang, Yumei Zhang, Hui Dong, Qingqing Sun, Lulu Tu, Yuchi Liao, Qianqian Feng, Li Yao, Lijun |
author_sort | Shu, Huapan |
collection | PubMed |
description | Introduction: Profibrotic phenotype of renal tubular epithelial cells (TECs) featured with epithelial to mesenchymal transition (EMT) and profibrotic factors secretion, and aberrant accumulation of CD206( + ) M2 macrophages are the key points in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Nevertheless, the underlying mechanisms involved remain incompletely understood. Serum and glucocorticoid-inducible kinase (SGK) is a serine/threonine protein kinase, required for intestinal nutrient transport and ion channels modulation. T-LAK-cell-originated protein kinase (TOPK) is a member of the mitogen activated protein kinase family, linked to cell cycle regulation. However, little is known about their roles in AKI-CKD transition. Methods: In this study, three models were constructed in C57BL/6 mice: low dose and multiple intraperitoneal injection of cisplatin, 5/6 nephrectomy and unilateral ureteral obstruction model. Rat renal tubular epithelial cells (NRK-52E) were dealt with cisplatin to induce profibrotic phenotype, while a mouse monocytic cell line (RAW264.7) were cultured with cisplatin or TGF-β1 to induce M1 or M2 macrophage polarization respectively. And co-cultured NRK-52E and RAW264.7 through transwell plate to explore the interaction between them. The expression of SGK3 and TOPK phosphorylation were detected by immunohistochemistry, immunofluorescence and western blot analysis. Results: In vivo, the expression of SGK3 and p-TOPK were gradually inhibited in TECs, but enhanced in CD206( + ) M2 macrophages. In vitro, SGK3 inhibition aggravated epithelial to mesenchymal transition through reducing the phosphorylation state of TOPK, and controlling TGF-β1 synthesis and secretion in TECs. However, SGK3/TOPK axis activation promoted CD206( + ) M2 macrophage polarization, which caused kidney fibrosis by mediating macrophage to myofibroblast transition (MMT). When co-cultured, the TGF-β1 from profibrotic TECs evoked CD206( + ) M2 macrophage polarization and MMT, which could be attenuated by SGK3/TOPK axis inhibition in macrophages. Conversely, SGK3/TOPK signaling pathway activation in TECs could reverse CD206( + ) M2 macrophages aggravated EMT. Discussion: We revealed for the first time that SGK3 regulated TOPK phosphorylation to mediate TECs profibrotic phenotype, macrophage plasticity and the crosstalk between TECs and macrophages during AKI-CKD transition. Our results demonstrated the inverse effect of SGK3/TOPK signaling pathway in profibrotic TECs and CD206( + ) M2 macrophages polarization during the AKI-CKD transition. |
format | Online Article Text |
id | pubmed-10285316 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102853162023-06-23 The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease Shu, Huapan Wang, Yumei Zhang, Hui Dong, Qingqing Sun, Lulu Tu, Yuchi Liao, Qianqian Feng, Li Yao, Lijun Front Pharmacol Pharmacology Introduction: Profibrotic phenotype of renal tubular epithelial cells (TECs) featured with epithelial to mesenchymal transition (EMT) and profibrotic factors secretion, and aberrant accumulation of CD206( + ) M2 macrophages are the key points in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Nevertheless, the underlying mechanisms involved remain incompletely understood. Serum and glucocorticoid-inducible kinase (SGK) is a serine/threonine protein kinase, required for intestinal nutrient transport and ion channels modulation. T-LAK-cell-originated protein kinase (TOPK) is a member of the mitogen activated protein kinase family, linked to cell cycle regulation. However, little is known about their roles in AKI-CKD transition. Methods: In this study, three models were constructed in C57BL/6 mice: low dose and multiple intraperitoneal injection of cisplatin, 5/6 nephrectomy and unilateral ureteral obstruction model. Rat renal tubular epithelial cells (NRK-52E) were dealt with cisplatin to induce profibrotic phenotype, while a mouse monocytic cell line (RAW264.7) were cultured with cisplatin or TGF-β1 to induce M1 or M2 macrophage polarization respectively. And co-cultured NRK-52E and RAW264.7 through transwell plate to explore the interaction between them. The expression of SGK3 and TOPK phosphorylation were detected by immunohistochemistry, immunofluorescence and western blot analysis. Results: In vivo, the expression of SGK3 and p-TOPK were gradually inhibited in TECs, but enhanced in CD206( + ) M2 macrophages. In vitro, SGK3 inhibition aggravated epithelial to mesenchymal transition through reducing the phosphorylation state of TOPK, and controlling TGF-β1 synthesis and secretion in TECs. However, SGK3/TOPK axis activation promoted CD206( + ) M2 macrophage polarization, which caused kidney fibrosis by mediating macrophage to myofibroblast transition (MMT). When co-cultured, the TGF-β1 from profibrotic TECs evoked CD206( + ) M2 macrophage polarization and MMT, which could be attenuated by SGK3/TOPK axis inhibition in macrophages. Conversely, SGK3/TOPK signaling pathway activation in TECs could reverse CD206( + ) M2 macrophages aggravated EMT. Discussion: We revealed for the first time that SGK3 regulated TOPK phosphorylation to mediate TECs profibrotic phenotype, macrophage plasticity and the crosstalk between TECs and macrophages during AKI-CKD transition. Our results demonstrated the inverse effect of SGK3/TOPK signaling pathway in profibrotic TECs and CD206( + ) M2 macrophages polarization during the AKI-CKD transition. Frontiers Media S.A. 2023-06-08 /pmc/articles/PMC10285316/ /pubmed/37361201 http://dx.doi.org/10.3389/fphar.2023.1169054 Text en Copyright © 2023 Shu, Wang, Zhang, Dong, Sun, Tu, Liao, Feng and Yao. 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 Shu, Huapan Wang, Yumei Zhang, Hui Dong, Qingqing Sun, Lulu Tu, Yuchi Liao, Qianqian Feng, Li Yao, Lijun The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title | The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title_full | The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title_fullStr | The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title_full_unstemmed | The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title_short | The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease |
title_sort | role of the sgk3/topk signaling pathway in the transition from acute kidney injury to chronic kidney disease |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285316/ https://www.ncbi.nlm.nih.gov/pubmed/37361201 http://dx.doi.org/10.3389/fphar.2023.1169054 |
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