PMID- 35836796 OWN - NLM STAT- MEDLINE DCOM- 20220718 LR - 20230111 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 12 IP - 11 DP - 2022 TI - DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. PG - 5069-5085 LID - 10.7150/thno.72291 [doi] AB - 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. CI - (c) The author(s). FAU - Xiong, Jiachuan AU - Xiong J AD - 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. FAU - Ran, Li AU - Ran L AD - 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. FAU - Zhu, Yingguo AU - Zhu Y AD - 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. FAU - Wang, Yaqin AU - Wang Y AD - 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. FAU - Wang, Shaobo AU - Wang S AD - 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. FAU - Wang, Yue AU - Wang Y AD - 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. FAU - Lan, Qigang AU - Lan Q AD - 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. FAU - Han, Wenhao AU - Han W AD - 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. FAU - Liu, Yong AU - Liu Y AD - 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. FAU - Huang, Yinghui AU - Huang Y AD - 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. FAU - He, Ting AU - He T AD - 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. FAU - Li, Yan AU - Li Y AD - 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. FAU - Liu, Li AU - Liu L AD - 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. FAU - Zhao, Jinghong AU - Zhao J AD - 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. FAU - Yang, Ke AU - Yang K AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220704 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - EC 3.1.3.48 (DUSP2 protein, human) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 2) SB - IM MH - *Acute Kidney Injury/metabolism MH - Animals MH - Dual Specificity Phosphatase 2/metabolism MH - Epithelial Cells/metabolism MH - Humans MH - Inflammation/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *Pyroptosis/physiology PMC - PMC9274747 OTO - NOTNLM OT - Acute kidney injury OT - DUSP2 OT - STAT1 OT - pyroptosis OT - renal tubular epithelial cell COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2022/07/16 06:00 MHDA- 2022/07/19 06:00 PMCR- 2022/01/01 CRDT- 2022/07/15 02:30 PHST- 2022/02/22 00:00 [received] PHST- 2022/06/25 00:00 [accepted] PHST- 2022/07/15 02:30 [entrez] PHST- 2022/07/16 06:00 [pubmed] PHST- 2022/07/19 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - thnov12p5069 [pii] AID - 10.7150/thno.72291 [doi] PST - epublish SO - Theranostics. 2022 Jul 4;12(11):5069-5085. doi: 10.7150/thno.72291. eCollection 2022.