PMID- 38237511 OWN - NLM STAT- MEDLINE DCOM- 20240214 LR - 20240214 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 125 DP - 2024 Mar TI - Astragaloside Ⅳ negatively regulates Gpr97-TPL2 signaling to protect against hyperhomocysteine-exacerbated sepsis associated acute kidney injury. PG - 155346 LID - S0944-7113(24)00011-4 [pii] LID - 10.1016/j.phymed.2024.155346 [doi] AB - BACKGROUND: Hyperhomocysteine (HHcy) plays an important role in promoting inflammation and cell death of tubular epithelial cells. However, the role of HHcy and Astragaloside IV (AS-IV) in sepsis associated acute kidney injury (S-AKI) remain unclear. PURPOSE: A significant aspect of this study aimed to elucidate the effect of AS-Ⅳ treatment on HHcy-exacerbated S-AKI and reveal its potential mechanism. METHODS: Male C57BL/6 J mice fed with specific diet containing 2% methionine were established as in vivo models, and AS-Ⅳ was orally administrated continuously for 3 weeks, and then LPS (10 mg.kg(-1) bodyweight) was given by a single intraperitoneal injection. The renal morphological changes were evaluated by HE and PAS staining. RNA-sequencing analysis was applied to select key signaling. The NRK-52E cells exposed to Hcy or combined with LPS were used as in vitro models. The mRNA and protein expression levels of Gpr97-TPL2 signaling were examined by qRT-PCR and western blotting assays. RESULTS: In vivo, HHcy mice developed more severe renal injury and prevalent tubular inflammation after LPS injection. In vitro, the levels of NGAL, Gpr97 and TPL2 were significantly increased in NRK-52E cells induced by Hcy (1.6 mM) or in combination with LPS. Notably, the effects of Hcy on TPL2 signaling was abolished by transfecting TPL2 siRNA or treating TPL2 inhibitor, without alterations in Gpr97. However, the enhancement of Gpr97-TPL2 signaling induced by Hcy was counteracted by Gpr97 siRNA. Subsequently, our findings demonstrated that AS-Ⅳ treatment can improve renal function in HHcy-exacerbated S-AKI mice. Mechanistically, AS-Ⅳ alleviated renal tubular damage characterized by abnormal increases in KIM-1, NGAL, TPL2, Gpr97, Sema3A and TNF-alpha, and decreases in survivin in vivo and in vitro mainly through suppressing the activation of Gpr97-TPL2 signaling. CONCLUSION: The present study suggested that HHcy-exacerbated S-AKI was mediated mechanically by activation of Gpr97-TPL2 signaling for the first time. Furthermore, our research also illustrated that AS-Ⅳ protected against HHcy-exacerbated S-AKI by attenuating renal tubular epithelial cells damage through negatively regulating Gpr97-TPL2 signaling, proposing a natural product treatment strategy for HHcy-exacerbated S-AKI. CI - Copyright (c) 2024. Published by Elsevier GmbH. FAU - Xu, Jingge AU - Xu J AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Zhang, Zhiyu AU - Zhang Z AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Ren, Dongwen AU - Ren D AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Liu, Luokun AU - Liu L AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Xing, Haitao AU - Xing H AD - The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China. FAU - Wang, Dan AU - Wang D AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Wu, Yuzheng AU - Wu Y AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Zhang, Yi AU - Zhang Y AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. FAU - Chen, Qian AU - Chen Q AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: qianchen89@tjutcm.edu.cn. FAU - Wang, Tao AU - Wang T AD - State Key Laboratory of Component Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: wangtao@tjutcm.edu.cn. LA - eng PT - Journal Article DEP - 20240108 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 3A592W8XKE (astragaloside A) RN - 0 (Lipocalin-2) RN - 0 (Lipopolysaccharides) RN - 0 (RNA, Small Interfering) RN - 0 (Saponins) RN - 0 (Triterpenes) SB - IM MH - Male MH - Mice MH - Animals MH - Lipocalin-2/adverse effects MH - Lipopolysaccharides/adverse effects MH - Mice, Inbred C57BL MH - *Acute Kidney Injury/chemically induced MH - *Sepsis/complications/drug therapy MH - RNA, Small Interfering MH - Inflammation MH - *Saponins MH - *Triterpenes OTO - NOTNLM OT - Astragaloside IV OT - Gpr97, TPL2 OT - Hyperhomocysteine OT - Sepsis associated AKI COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/01/19 00:42 MHDA- 2024/02/12 05:43 CRDT- 2024/01/18 18:14 PHST- 2023/10/12 00:00 [received] PHST- 2023/12/25 00:00 [revised] PHST- 2024/01/07 00:00 [accepted] PHST- 2024/02/12 05:43 [medline] PHST- 2024/01/19 00:42 [pubmed] PHST- 2024/01/18 18:14 [entrez] AID - S0944-7113(24)00011-4 [pii] AID - 10.1016/j.phymed.2024.155346 [doi] PST - ppublish SO - Phytomedicine. 2024 Mar;125:155346. doi: 10.1016/j.phymed.2024.155346. Epub 2024 Jan 8.