SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury
Abstract Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04131-7 |
| _version_ | 1819067614951899136 |
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| author | Lin-Li Lv Cui Wang Zuo-Lin Li Jing-Yuan Cao Xin Zhong Ye Feng Jun Chen Tao-Tao Tang Hai-Feng Ni Qiu-Li Wu Bin Wang Hui-Yao Lan Bi-Cheng Liu |
| author_facet | Lin-Li Lv Cui Wang Zuo-Lin Li Jing-Yuan Cao Xin Zhong Ye Feng Jun Chen Tao-Tao Tang Hai-Feng Ni Qiu-Li Wu Bin Wang Hui-Yao Lan Bi-Cheng Liu |
| author_sort | Lin-Li Lv |
| collection | DOAJ |
| description | Abstract Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3′-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI. |
| first_indexed | 2024-12-21T16:21:04Z |
| format | Article |
| id | doaj.art-50af5ecc5f8d457b96f1414b614b6a16 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-21T16:21:04Z |
| publishDate | 2021-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-50af5ecc5f8d457b96f1414b614b6a162022-12-21T18:57:34ZengNature Publishing GroupCell Death and Disease2041-48892021-09-01121011110.1038/s41419-021-04131-7SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injuryLin-Li Lv0Cui Wang1Zuo-Lin Li2Jing-Yuan Cao3Xin Zhong4Ye Feng5Jun Chen6Tao-Tao Tang7Hai-Feng Ni8Qiu-Li Wu9Bin Wang10Hui-Yao Lan11Bi-Cheng Liu12Institute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineDepartment of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative RegionInstitute of Nephrology, Zhongda Hospital, Southeast University School of MedicineAbstract Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3′-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.https://doi.org/10.1038/s41419-021-04131-7 |
| spellingShingle | Lin-Li Lv Cui Wang Zuo-Lin Li Jing-Yuan Cao Xin Zhong Ye Feng Jun Chen Tao-Tao Tang Hai-Feng Ni Qiu-Li Wu Bin Wang Hui-Yao Lan Bi-Cheng Liu SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury Cell Death and Disease |
| title | SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury |
| title_full | SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury |
| title_fullStr | SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury |
| title_full_unstemmed | SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury |
| title_short | SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury |
| title_sort | sap130 released by damaged tubule drives necroinflammation via mirna 219c mincle signaling in acute kidney injury |
| url | https://doi.org/10.1038/s41419-021-04131-7 |
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