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Theranostics 2022; 12(11):5069-5085. doi:10.7150/thno.72291 This issue Cite

Research Paper

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Jiachuan Xiong#, Li Ran#, Yingguo Zhu, Yaqin Wang, Shaobo Wang, Yue Wang, Qigang Lan, Wenhao Han, Yong Liu, Yinghui Huang, Ting He, Yan Li, Li Liu, Jinghong Zhao✉, Ke Yang✉

Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, P.R. China.
#These authors contributed equally to this work.

✉ Corresponding authors: Ke Yang, PhD, or Jinghong Zhao, MD, PhD, Department of Nephrology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China. E-mail: keyangedu.cn or zhaojhedu.cn. Tel: More

Citation:
Xiong J, Ran L, Zhu Y, Wang Y, Wang S, Wang Y, Lan Q, Han W, Liu Y, Huang Y, He T, Li Y, Liu L, Zhao J, Yang K. DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics 2022; 12(11):5069-5085. doi:10.7150/thno.72291. https://www.thno.org/v12p5069.htm
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Abstract

Graphic abstract

Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown.

Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro, and confirmed in RTEC-specific deletion of DUSP2 mice.

Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI.

Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.

Keywords: Acute kidney injury, renal tubular epithelial cell, DUSP2, pyroptosis, STAT1

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APA
Xiong, J., Ran, L., Zhu, Y., Wang, Y., Wang, S., Wang, Y., Lan, Q., Han, W., Liu, Y., Huang, Y., He, T., Li, Y., Liu, L., Zhao, J., Yang, K. (2022). DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics, 12(11), 5069-5085. https://doi.org/10.7150/thno.72291.

ACS
Xiong, J.; Ran, L.; Zhu, Y.; Wang, Y.; Wang, S.; Wang, Y.; Lan, Q.; Han, W.; Liu, Y.; Huang, Y.; He, T.; Li, Y.; Liu, L.; Zhao, J.; Yang, K. DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics 2022, 12 (11), 5069-5085. DOI: 10.7150/thno.72291.

NLM
Xiong J, Ran L, Zhu Y, Wang Y, Wang S, Wang Y, Lan Q, Han W, Liu Y, Huang Y, He T, Li Y, Liu L, Zhao J, Yang K. DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics 2022; 12(11):5069-5085. doi:10.7150/thno.72291. https://www.thno.org/v12p5069.htm

CSE
Xiong J, Ran L, Zhu Y, Wang Y, Wang S, Wang Y, Lan Q, Han W, Liu Y, Huang Y, He T, Li Y, Liu L, Zhao J, Yang K. 2022. DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Theranostics. 12(11):5069-5085.

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