The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease

作者全名："Shu, Huapan; Wang, Yumei; Zhang, Hui; Dong, Qingqing; Sun, Lulu; Tu, Yuchi; Liao, Qianqian; Feng, Li; Yao, Lijun"

作者地址："[Shu, Huapan; Wang, Yumei; Zhang, Hui; Dong, Qingqing; Sun, Lulu; Tu, Yuchi; Liao, Qianqian; Feng, Li; Yao, Lijun] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Nephrol, Wuhan, Hubei, Peoples R China; [Dong, Qingqing] Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing, Peoples R China"

通信作者："Yao, LJ (通讯作者)，Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Nephrol, Wuhan, Hubei, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001017304000001

JCR分区：Q1

影响因子：4.4

年份：2023

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：acute kidney injury; chronic kidney disease; macrophages; renal tubular epithelial cells; epithelial-to-mesenchymal transition; macrophage-to-myofibroblast transition

摘要："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-beta 1 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-ss 1 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-beta 1 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."

基金机构："National Natural Science Foundation of China [81974102, 81570657]"

基金资助正文：This work was supported by the fund from the National Natural Science Foundation of China (Nos 81974102 and 81570657).