S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3\u03b2 and CK1\u03b1

Yifei Sun,Ya Fan,Xiubin Liang,Min Li,Yun Liu,Dongming Su,Zheng Wang

doi:10.1007/s00018-022-04213-5

Abstract

The pathogenesis of acute kidney injury (AKI) is associated with the activation of multiple signaling pathways, including Wnt/β-catenin signaling. However, the mechanism of Wnt/β-catenin pathway activation in renal interstitial fibroblasts during AKI is unclear. S100 calcium-binding protein A16 (S100A16), a new member of calcium-binding protein S100 family, is a multi-functional signaling factor involved in various pathogenies, including tumors, glycolipid metabolism disorder, and chronic kidney disease (CKD). We investigated the potential participation of S100A16 in Wnt/β-catenin pathway activation during AKI by subjecting wild-type (WT) and S100A16 knockout (S100A16+/−) mice to the ischemia–reperfusion injury (IRI), and revealed S100A16 upregulation in this model, in which knockout of S100A16 impeded the Wnt/β-catenin signaling pathway activation and recovered the expression of downstream hepatocyte growth factor (HGF). We also found that S100A16 was highly expressed in Platelet-derived growth factor receptor beta (PDGFRβ) positive renal fibroblasts in vivo. Consistently, in rat renal interstitial fibroblasts (NRK-49F cells), both hypoxia/reoxygenation and S100A16 overexpression exacerbated fibroblasts apoptosis and inhibited HGF secretion; whereas S100A16 knockdown or Wnt/β-catenin pathway inhibitor ICG-001 reversed these changes. Mechanistically, we showed that S100A16 promoted Wnt/β-catenin signaling activation via the ubiquitylation and degradation of β-catenin complex members, glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α), mediated by E3 ubiquitin ligase, the HMG-CoA reductase degradation protein 1 (HRD1). Our study identified the S100A16 as a key regulator in the activation of Wnt/β-catenin signaling pathway in AKI.

Highlights

acute kidney injury (AKI) is associated with high morbidity and mortality, claiming about 1.7 million lives worldwide each year [1]
We have reported that the protein expression of S100 calcium-binding protein A16 (S100A16) is significantly increased in the kidneys of unilateral ureteral occlusion (UUO) mice and the characteristic pathological changes of renal tubulointerstitial fibrosis appeared in the kidney of S100A16 transgenic mice, indicating a positive relationship between S100A16 and tubulointerstitial fibrosis
We investigated the pathogenic relevance of S100A16 in AKI by first examining the S100A16 protein expression in the kidney tissues in WT mice and S100A16+/− mice with or without an ischemia–reperfusion injury (IRI) procedure

Summary

Introduction

AKI is associated with high morbidity and mortality, claiming about 1.7 million lives worldwide each year [1]. AKI is clinically considered a rapid decline in renal function from a variety of causes, of which IRI is widely considered the most important cause [2]. Considered a self-healing disease, recent studies have shown that severe AKI leads to incomplete renal repair, persistent chronic inflammation, fibrosis progression, and eventually chronic organ loss [3, 4]. The long-term consequences of AKI include CKD and even serious end-stage renal disease (ESRD), both associated with a poor quality of life and high cost of care, thereby imposing a significant burden on the society [5, 6]. Multiple signaling pathways contribute to the pathogenesis of AKI. The activation of Wnt/β-catenin pathway plays an irreplaceable role in severe AKI. When the kidney is subjected to IRI, Wnt/β-catenin signaling is activated in the cells of the kidney [11, 12]. In the canonical Wnt/β-catenin signaling pathway, the transcriptional coactivator β-catenin is regulated by the β-catenin

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