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.