1 | INTRODUCTION
Acute kidney injury (AKI) is the sudden loss of excretory kidney function. AKI is one of the various functional kidney conditions, which are summarized as acute kidney disease and disorders (AKD), in which slow deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD) (Kellum, Romagnani, Ashuntantang, Ronco, Zarbock & Anders, 2021). Various types of abuse, such as ischemia, toxin exposure, and infection, can provoke kidney injury. Aristolochic acid (AA), an important cause of drug-related renal injury, has been reported to cause a range of serious health problems, including tubular necrosis, renal failure, and urothelial carcinoma (Debelle, Vanherweghem & Nortier, 2008; Vanherweghem et al., 1993). Aristolochic acid nephropathy (AAN) is characterized by extensive tubular epithelial cell (TEC) injury in both patients and animal models of AAN (Pozdzik et al., 2008; Wang, Xue, Zhao, Shi, Ding & Fang, 2020). However, the molecular mechanisms underlying tubular epithelial cell injury in AA-related renal injury remain unclear.
Several studies have indicated that various types of programmed cell death, such as apoptosis, necroptosis, and pyroptosis, are involved in maintaining the homeostasis of kidney tissue and participating in the pathogenesis of AKI (Bonventre & Yang, 2011). We previously reported that aristolochic acid-induced tubular damage and apoptosis are the primary insults in AAN. Baudoux et al. reported that human AAN is a tubulointerstitial (TI) nephritis reported after consuming herbal remedies containing aristolochic acid (Baudoux et al., 2022). In the early acute phase, tubular necrosis in proximal tubular epithelial cells (PTECs) is observed. Deng et al. demonstrated that aristolochic acid causes ferroptosis in HK-2 cells, providing new insights into the toxic mechanisms underlying aristolochic acid-triggered nephrotoxicity (Deng et al., 2020). Cells carry out multiple regulated cell death programs via extensive crosstalk, which can be activated simultaneously under specific conditions. This is consistent with the recently proposed concept of “PANoptosis.” However, the role of PANoptosis in AAN has not been elucidated.
Recent studies in several animal models suggest that HDAC inhibitors can protect against diabetic nephropathy (Christensen et al., 2011), suppress kidney fibrosis in a unilateral ureteral ligation model (Liu et al., 2013), enhance kidney recovery from AKI (Cianciolo Cosentino et al., 2013), and suppress inflammation and kidney injury in the MRL-lpr/lpr mouse(Mishra, Reilly, Brown, Ruiz & Gilkeson, 2003). Yao et al. provided evidence that HDAC11 promotes NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways, leading to vascular endothelial cell pyroptosis (Yao et al., 2022). Wang et al. reported that HDAC inhibitors could initiate cell autophagy by inhibiting Akt and mTOR, which play important roles in protecting cells from necroptosis (Wang et al., 2013). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from specific lysine residues on cellular and DNA binding proteins, such as histones, to regulate protein function, chromatin architecture, and gene expression (Chen et al., 2011).
In this study, we found that administration of the HDAC inhibitor FK-228 suppressed the tubular epithelial cell PANoptosis. The protective activity of the HDAC inhibitor was mediated through the upregulation of PSTPIP2 in tubular epithelial cells, which may provide some evidence for potential complement treatments in AAN therapy that target PSTPIP2.