Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation
Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet th...
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Elsevier
2025-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000489 |
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| author | Yanshan Chen Yuanxing Zhi Hailin Zhong Liang Ma Xinpei Gu Yijing Cai Jingjing Huang Xin Yi Xiaoyan Wu Ken Kin Lam Yung Pingzheng Zhou |
| author_facet | Yanshan Chen Yuanxing Zhi Hailin Zhong Liang Ma Xinpei Gu Yijing Cai Jingjing Huang Xin Yi Xiaoyan Wu Ken Kin Lam Yung Pingzheng Zhou |
| author_sort | Yanshan Chen |
| collection | DOAJ |
| description | Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases. |
| format | Article |
| id | doaj-art-7c2d26c9acd24e849c0f6c751f51fc39 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-7c2d26c9acd24e849c0f6c751f51fc392025-02-06T05:11:05ZengElsevierPharmacological Research1096-11862025-03-01213107623Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylationYanshan Chen0Yuanxing Zhi1Hailin Zhong2Liang Ma3Xinpei Gu4Yijing Cai5Jingjing Huang6Xin Yi7Xiaoyan Wu8Ken Kin Lam Yung9Pingzheng Zhou10NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, ChinaDepartment of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, ChinaProvincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, Department of Science and Environmental Studies, the Education University of Hong Kong, Hong Kong, ChinaNMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China; Corresponding author at: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China.Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases.http://www.sciencedirect.com/science/article/pii/S1043661825000489Kv1.3Potassium channelMacrophageM2 polarizationSTAT6Renal fibrosis |
| spellingShingle | Yanshan Chen Yuanxing Zhi Hailin Zhong Liang Ma Xinpei Gu Yijing Cai Jingjing Huang Xin Yi Xiaoyan Wu Ken Kin Lam Yung Pingzheng Zhou Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation Pharmacological Research Kv1.3 Potassium channel Macrophage M2 polarization STAT6 Renal fibrosis |
| title | Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation |
| title_full | Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation |
| title_fullStr | Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation |
| title_full_unstemmed | Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation |
| title_short | Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation |
| title_sort | inhibition of kv1 3 channel restrains macrophage m2 polarization and ameliorates renal fibrosis via regulating stat6 phosphorylation |
| topic | Kv1.3 Potassium channel Macrophage M2 polarization STAT6 Renal fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000489 |
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