Abstract
Stratifin (SFN) is a member of the 14-3-3 family of highly conserved soluble acidic proteins, which regulates a variety of cellular activities such as cell cycle, cell growth and development, cell survival and death, and gene transcription. Acute kidney injury (AKI) is prevalent disorder characterized by inflammatory response, oxidative stress, and programmed cell death in renal tubular epithelial cells, but there is still a lack of effective therapeutic target for AKI. In this study, we investigated the role of SFN in AKI and the underlying mechanisms. We established ischemic and nephrotoxic AKI mouse models caused by ischemia–reperfusion (I/R) and cisplatin, respectively. We conducted proteomic and immunohistochemical analyses and found that SFN expression levels were significantly increased in AKI patients, cisplatin- or I/R-induced AKI mice. In cisplatin- or hypoxia/reoxygenation (H/R)-treated human proximal tubule epithelial cells (HK2), we showed that knockdown of SFN significantly reduced the expression of kidney injury marker Kim-1, attenuated programmed cell death and inflammatory response. Knockdown of SFN also significantly alleviated the decline of renal function and histological damage in cisplatin-caused AKI mice in vivo. We further revealed that SFN bound to RIPK3, a key signaling modulator in necroptosis, to induce necroptosis and the subsequent inflammation in cisplatin- or H/R-treated HK2 cells. Overexpression of SFN increased Kim-1 protein levels in cisplatin-treated MTEC cells, which was suppressed by RIPK3 knockout. Taken together, our results demonstrate that SFN that enhances cisplatin- or I/R-caused programmed cell death and inflammation via interacting with RIPK3 may serve as a promising therapeutic target for AKI treatment.
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Acknowledgements
We thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment. This work was supported by the National Natural Science Foundation of China (No. 81970584). Promotion plan of basic and clinical cooperative research in Anhui Medical University (No. 2019xkjT014; No. 2020xkjT016).
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FW, JNW, and XYH performed the cell experiment, analyzed the data, and wrote the manuscript. XMM and JJ designed, supervised, and wrote the manuscript. CL, WJN, YTC, XZ, and YRY provided a series of experimental instructions and help. XGS, YH, XYF, and YHD performed the animal experiments. FZ, TX, HMZ, MML, and JL contributed new reagents or analytic tools.
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Wang, F., Wang, Jn., He, Xy. et al. Stratifin promotes renal dysfunction in ischemic and nephrotoxic AKI mouse models via enhancing RIPK3-mediated necroptosis. Acta Pharmacol Sin 43, 330–341 (2022). https://doi.org/10.1038/s41401-021-00649-w
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DOI: https://doi.org/10.1038/s41401-021-00649-w
