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 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.

• Authors: 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
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 10 Pg. 866 (09 23 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34556635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• 3' Untranslated Regions
• Clecsf8 protein, mouse
• Cytokines
• Lectins, C-Type
• MIRN219 microRNA, mouse
• Membrane Proteins
• MicroRNAs
• RNA Splicing Factors
• Sf3b3 protein, mouse

Topics

• 3' Untranslated Regions (genetics)
• Acute Kidney Injury (genetics, pathology)
• Adult
• Animals
• Base Sequence
• Case-Control Studies
• Cell Death
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Humans
• Inflammation (pathology)
• Kidney Tubules (pathology)
• Lectins, C-Type (genetics, metabolism)
• Macrophage Activation
• Macrophages (metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Necrosis
• RAW 264.7 Cells
• RNA Splicing Factors (metabolism)
• Signal Transduction