SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury

Lin-Li Lv,Ye Feng,Jing-Yuan Cao,Jun Chen,Qiu-Li Wu,Zuo-Lin Li,Tao-Tao Tang,Hui-Yao Lan,Cui Wang,Xin Zhong,Bi-Cheng Liu,Bin Wang,Hai-Feng Ni

doi:10.1038/s41419-021-04131-7

Lin-Li Lv, Ye Feng + Show 11 more

Open Access

https://doi.org/10.1038/s41419-021-04131-7

Copy DOI

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.

Highlights

Acute kidney injury (AKI) is characterized by a complex interacting process including cell death, infiltration of immune cells, and the following cellular maladaptive repair processes [1]
We found that spliceosome associated protein 130 (SAP130) together, these results suggested that SAP130 from dead tubular epithelial cells (TECs) was capable of promoting macrophage activation and interstitial inflammation via Macrophage inducible C-type lectin (Mincle) signaling
Mincle is a C-type lectin receptor that senses cell death and induces the production of inflammatory cytokines to drive the infiltration of inflammatory cells into damaged tissue

Summary

Introduction

Acute kidney injury (AKI) is characterized by a complex interacting process including cell death, infiltration of immune cells, and the following cellular maladaptive repair processes [1]. Macrophages are considered to be key inflammatory cells that participated in the progression and repair of AKI [4]. Damage-associated molecular patterns (DAMPs) are endogenous molecules released upon cellular activation, stress, or damage and can induce the activation of inflammatory pathways during sterile inflammation [5]. Accumulating evidence suggested that a variety of DAMPs released from dead cells triggered immune responses and contributed to the pathogenesis of kidney disease [6,7,8,9]. DAMPs initiate kidney inflammation through recognizing their respective pattern recognition receptors (PRRs), including Toll-like receptors, purinergic receptors, or the NLRP3 inflammasome [6]

Objectives

Methods

Findings

Conclusion