ABSTRACT
Background and Purpose: Aristolochic acid nephropathy (AAN) is
a progressive kidney disease caused by using herbal medicines.
Currently, no therapies are available to treat or prevent AAN. Histone
deacetylase (HDAC) plays a crucial role in the development and
progression of renal disease. We tested whether HDAC inhibitors could
prevent AAN and determined the underlying mechanism.
Experimental Approach: HDACs expression in the kidneys was
examined. Mouse kidney and renal tubular epithelial cell damage were
assessed after exposure to HDAC1 and HDAC2 blockade (FK-228).
Conditional knock-in of Proline-serine-threonine-phosphatase-interacting
protein 2 (PSTPIP2) in the kidney and knockdown of PSTPIP2 expression in
PSTPIP2-knockin mice, pathological parameters, and kidney injuries were
assessed.
Key Results: Aristolochic acid upregulated the expression of
HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and -2 specific
inhibitor, romidepsin (FK228, Depsipeptide), suppressed aristolochic
acid-induced kidney injury, epithelial cell pyroptosis, apoptosis, and
necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in
renal tubular epithelial cells, which was enhanced by aristolochic acid
treatment. Conditional knock-in of PSTPIP2 in the kidney protected
against AAN. In contrast, the knockdown of PSTPIP2 expression in
PSTPIP2-knockin mice restored kidney damage and PANoptosis. PSTPIP2
function was determined in vitro using PSTPIP2 knockdown or
overexpression in mTEC. Additionally, PSTPIP2 was found to regulate
Caspase-8 in Aristolochic acid nephropathy.
Conclusion and Implications: HDAC-mediated silencing of PSTPIP2
may contribute to aristolochic acid nephropathy. Hence, HDAC1 and -2
specific inhibitors or PSTPIP2 could be valuable therapeutic agents for
the prevention of aristolochic acid nephropathy.