S100A16 Promotes Acute Kidney Injury By Activating HRD1-Induced Ubiquitination And Degradation of GSK3β And CK1α

Abstract

The pathogenesis of acute kidney injury (AKI) is associated with 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 α-SMA positive renal fibroblasts in vivo. Consistently, in rat renal interstitial fibroblasts (NRK-49F cells), both hypoxia 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 show that S100A16 promotes 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.

Proximal tubular FHL2, a novel downstream target of hypoxia inducible factor 1, is a protector against ischemic acute kidney injury

“…Cells were cultured in DMEM/F12 medium supplemented with 5% fetal bovine serum (Invitrogen, USA). To establish a model of hypoxia, cells were cultured in an airtight anoxia jar in which a hypoxic environment was maintained using a MGC AnaeroPack system (Mitsubishi Gas Chemical Corporation, Tokyo, Japan) [42]. Specifically, AnaeroPack served as an O 2 absorber and CO 2 generator.…”