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 chronic k...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1169054/full |
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| author | Huapan Shu Yumei Wang Hui Zhang Qingqing Dong Qingqing Dong Lulu Sun Yuchi Tu Qianqian Liao Li Feng Lijun Yao |
| author_facet | Huapan Shu Yumei Wang Hui Zhang Qingqing Dong Qingqing Dong Lulu Sun Yuchi Tu Qianqian Liao Li Feng Lijun Yao |
| author_sort | Huapan Shu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T06:46:32Z |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T06:46:32Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-99d9496f119940659d9873735785f7df2023-06-08T05:33:54ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-06-011410.3389/fphar.2023.11690541169054The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney diseaseHuapan Shu0Yumei Wang1Hui Zhang2Qingqing Dong3Qingqing Dong4Lulu Sun5Yuchi Tu6Qianqian Liao7Li Feng8Lijun Yao9Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaIntroduction: 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1169054/fullacute kidney injurychronic kidney diseasemacrophagesrenal tubular epithelial cellsepithelial-to-mesenchymal transitionmacrophage-to-myofibroblast transition |
| spellingShingle | Huapan Shu Yumei Wang Hui Zhang Qingqing Dong Qingqing Dong Lulu Sun Yuchi Tu Qianqian Liao Li Feng Lijun Yao The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease Frontiers in Pharmacology acute kidney injury chronic kidney disease macrophages renal tubular epithelial cells epithelial-to-mesenchymal transition macrophage-to-myofibroblast transition |
| 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 | acute kidney injury chronic kidney disease macrophages renal tubular epithelial cells epithelial-to-mesenchymal transition macrophage-to-myofibroblast transition |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1169054/full |
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