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PSTPIP2 Inhibits Cisplatin-Induced Acute Kidney Injury by Suppressing

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PSTPIP2 Inhibits Cisplatin-Induced Acute Kidney Injury by Suppressing Zhu et al. Cell Death and Disease (2020) 11:1057 https://doi.org/10.1038/s41419-020-03267-2 Cell Death & Disease ARTICLE Open Access PSTPIP2 inhibits cisplatin-induced acute kidney injury by suppressing apoptosis of renal tubular epithelial cells Hong Zhu1, Wenjuan Jiang1,HuiziZhao1, Changsheng He1, Xiaohan Tang1, Songbing Xu1,ChuantingXu1,RuiFeng1, Jun Li1,TaotaoMa1 and Cheng Huang1 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) 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; 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. Introduction side effects of cisplatin3,4. The existing therapy for cis- Cisplatin is one of the most generally used and highly platin nephrotoxicity in humans does not completely effective chemotherapy drugs for the treatment of various prevent AKI occurrence5,6. Therefore, there is an urgent types of human cancer, such as testicular, ovarian, head need to find an effective therapy based on the mechanism and neck, bladder, bone, muscle, small and non-small cell of cisplatin nephrotoxicity. lung and cervical cancers, sarcomas and lymphomas1,2. Apoptosis of tubular epithelial cells and renal inflam- Unfortunately, the clinical application of cisplatin is mation have been shown to be a prominent and char- severely limited by considerable side effects associated acteristic feature of cisplatin-induced AKI7,8. Recent with nephrotoxicity, which is one of the most common studies suggested that proline–serine–threonine phosphatase-interacting protein 2 (PSTPIP2) has immu- nomodulatory activity and is closely associated with cell 9–11 Correspondence: Taotao Ma ([email protected])or proliferation and apoptosis . PSTPIP2 is a member of Cheng Huang ([email protected]) the Pombe Cdc15 homology (PCH) family of proteins 1 fl In ammation and Immune Mediated Diseases Laboratory of Anhui Province, located on chromosome 18 and is known as a protein Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China important for the organisation of the cytoskeleton at the Edited by B. Zhivotovsky © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhu et al. Cell Death and Disease (2020) 11:1057 Page 2 of 13 cell membrane12,13. PSTPIP2 is expressed in various and blood urea nitrogen (BUN) levels were significantly organs and tissues, such as brain, heart, kidney, lung, liver, increased in the CP group (Fig. 1c, d). These results etc. At the cellular level, the expression of PSTPIP2 was suggest that CP induced significant lesions. Western blot detected in monocytes, lymphocytes, granulocytes and analysis showed that KIM-1 (kidney injury molecule-1) mast cells. PSTPIP2 plays an imperative role in tumours, was upregulated in the kidneys of the CP group (Fig. 1e). autoimmune diseases and other diseases by influencing The protein level of PSTPIP2 in the kidney tissue of the cell proliferation, apoptosis and secretion of inflammatory CP group was decreased (Fig. 1f). Renal tubular epithelial – factors14 18. Ales Drobek et al. showed that PSTPIP2 cells were reported as the main site of cell injury during binds lipid phosphatase SHIP1 and protein tyrosine kinase cisplatin nephrotoxicity. Then, we used HK-2 cells to Csk (negative regulators of inflammation) to prevent the induce acute kidney injury in vitro. CP at 2.5, 5, 10, 15 and development of auto-inflammation. Baum et al. reported 20 μM concentrations was used to determine the optimal that PSTPIP2 can bind and interact with the intracellular concentration of cisplatin. As shown in Fig. 2a, b, the FasL domain, regulate FasL localisation in the cytoplasm, protein levels of KIM-1 and PSTPIP2 were increased and and coordinate apoptosis of HEK 293T, COS-1, RBL2H3 decreased, respectively, in a dose-dependent manner after and other cells. Moreover, Halle et al. found that PSTPIP2 the treatment with cisplatin. Therefore, the concentra- controls the function of activated caspase-3 by acting as a tions of cisplatin in the subsequent experiment in HK-2 substrate of PTP-PEST and plays an important role in cell cells were 20 μM. Western blot analysis showed that KIM- apoptosis10,19,20. These studies suggest that investigation 1 is significantly upregulated in CP-treated HK-2 cells of the effect of PSTPIP2 on apoptosis of renal tubular (Fig. 2c). Moreover, western blot results demonstrated epithelial cells can promote the understanding of the that the expression of PSTPIP2 was downregulated in CP- pathogenesis of cisplatin-induced AKI and provide ideas treated HK-2 cells (Fig. 2d). Similar patterns of KIM-1 and for clinical prevention and treatment of cisplatin-induced PSTPIP2 expression were demonstrated by immuno- AKI to identify new drug targets. fluorescence staining (Fig. 2e, f). Collectively, these results In this study, we investigated whether PSTPIP2 can suggest that PSTPIP2 expression is decreased in cisplatin- suppress cisplatin nephrotoxicity and what are the treated mice and in cisplatin-treated HK-2 cells. mechanisms of this effect. Our results show that admin- istration of AAV-PSTPIP2 or epithelial cell-specific PSTPIP2 administration suppressed cisplatin-induced overexpression of PSTPIP2 reduces cisplatin-induced kidney dysfunction kidney dysfunction and inhibits apoptosis of renal tubu- To examine the functional importance of PSTPIP2 in lar epithelial cells. Interestingly, we have detected that the progressive kidney injury in a mouse model of AKI, histone H3 acetylated at lysine 27 (H3K27ac) binds to the rAAV9–PSTPIP2 was confirmed as an efficient means of PSTPIP2 promoter. Furthermore, an HDAC inhibitor delivery in CP-treated AKI mice (Fig. 3a, b). Macro- trichostatin A (TSA) can upregulated PSTPIP2 in vivo scopically, rAAV9–PSTPIP2 can significantly improve and in vitro. In conclusion, this study is the first to renal function, which is related to improved preservation demonstrate that PSTPIP2 plays a pivotal role in AKI and of kidney morphology. Histological analysis with periodic may be a potential therapeutic target for cisplatin acid-Schiff (PAS) staining revealed a significant decrease nephrotoxicity. in the tissue damage in the rAAV9–PSTPIP2 group compared to that in the CP group (Fig. 3c). Body weight in Results the rAAV9–PSTPIP2 group was slightly increased com- PSTPIP2 was downregulated in vivo and in vitro pared to that in the CP group and was close to that in the To explore the role of PSTPIP2 in cisplatin-induced normal group (Fig. 3d). Consistently, an increase in the Cr acute kidney injury (AKI) model, AKI mice model was and BUN levels was significantly attenuated by initially validated by assessing the effects of cisplatin on rAAV9–PSTPIP2 (Fig. 3e, f). Western blot analysis the renal injury markers and the levels of PSTPIP2 on the showed that KIM-1 protein expression was significantly third day after intraperitoneal injection21. Histopatholo- upregulated in the CP treatment group, and gical changes are direct indicators of kidney injury. The rAAV9–PSTPIP2 can reduce the expression of KIM-1 mice had messy fur and slow movements on the third day protein (Fig. 3g). These results indicate that
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