Abstract
Cisplatin (CP) is an effective chemotherapeutic agent widely used in the treatment of various solid tumours. However, CP nephrotoxicity is an important limitation for CP use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Recently, we identified a specific role of proline–serine–threonine phosphatase-interacting protein 2 (PSTPIP2) in cisplatin-induced AKI. PSTPIP2 was reported to play an important role in a variety of diseases. However, the functions of PSTPIP2 in experimental models of cisplatin-induced AKI have not been extensively studied. The present study demonstrated that cisplatin downregulated the expression of PSTPIP2 in the kidney tissue. Administration of AAV-PSTPIP2 or epithelial cell-specific overexpression of PSTPIP2 reduced cisplatin-induced kidney dysfunction and inhibited apoptosis of renal tubular epithelial cells. Small interfering RNA-based knockdown of PSTPIP2 expression abolished PSTPIP2 regulation of epithelial cell apoptosis in vitro. Histone acetylation may impact gene expression at the epigenetic level, and histone deacetylase (HDAC) inhibitors were reported to prevent cisplatin-induced nephrotoxicity. The UCSC database was used to predict that acetylation of histone H3 at lysine 27 (H3K27ac) induces binding to the PSTPIP2 promoter, and this prediction was validated by a ChIP assay. Interestingly, an HDAC-specific inhibitor (TSA) was sufficient to potently upregulate PSTPIP2 in epithelial cells. Histone acetylation-mediated silencing of PSTPIP2 may contribute to cisplatin nephrotoxicity. PSTPIP2 may serve as a potential therapeutic target in the prevention of cisplatin nephrotoxicity.
Highlights
Cisplatin is one of the most generally used and highly effective chemotherapy drugs for the treatment of various types of human cancer, such as testicular, ovarian, head and neck, bladder, bone, muscle, small and non-small cell lung and cervical cancers, sarcomas and lymphomas[1,2]
proline–serine–threonine phosphatase-interacting protein 2 (PSTPIP2) was downregulated in vivo and in vitro To explore the role of PSTPIP2 in cisplatin-induced acute kidney injury (AKI) model, AKI mice model was initially validated by assessing the effects of cisplatin on the renal injury markers and the levels of PSTPIP2 on the third day after intraperitoneal injection[21]
PSTPIP2 in AKI and identified a potential mechanism of PSTPIP2 inhibition of epithelial apoptosis to alleviate the nephrotoxicity of cisplatin
Summary
Cisplatin is one of the most generally used and highly effective chemotherapy drugs for the treatment of various types of human cancer, such as testicular, ovarian, head and neck, bladder, bone, muscle, small and non-small cell lung and cervical cancers, sarcomas and lymphomas[1,2]. Halle et al found that PSTPIP2 controls the function of activated caspase-3 by acting as a substrate of PTP-PEST and plays an important role in cell apoptosis[10,19,20]. These studies suggest that investigation of the effect of PSTPIP2 on apoptosis of renal tubular epithelial cells can promote the understanding of the pathogenesis of cisplatin-induced AKI and provide ideas for clinical prevention and treatment of cisplatin-induced AKI to identify new drug targets
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