PMID- 33857849 OWN - NLM STAT- MEDLINE DCOM- 20210602 LR - 20240226 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 86 DP - 2021 Jun TI - Vitexin exerts protective effects against calcium oxalate crystal-induced kidney pyroptosis in vivo and in vitro. PG - 153562 LID - S0944-7113(21)00104-5 [pii] LID - 10.1016/j.phymed.2021.153562 [doi] AB - BACKGROUND: Nephrolithiasis is a common urinary disease with a high recurrence rate of secondary stone formation. Several mechanisms are involved in the onset and recurrence of nephrolithiasis, e.g., oxidative stress, inflammation, apoptosis, and epithelial-mesenchymal transition (EMT). Vitexin, a flavonoid monomer derived from medicinal plants that exert many biological effects including anti-inflammatory and anticancer effects, has not been investigated in nephrolithiasis studies. Moreover, pyroptosis, a form of programmed cell death resulting from inflammasome-associated caspase activation, has not been studied in mice with nephrolithiasis. PURPOSE: We aimed to investigate the protective effect and underlying mechanisms of vitexin in nephrolithiasis, and the related role of pyroptosis in vivo and in vitro. METHODS: Mouse models of nephrolithiasis were established via intraperitoneal injection of glyoxylate, and cell models of tubular epithelial cells and macrophages were established using calcium oxalate monohydrate (COM). Crystal deposition and kidney tissue injury were evaluated by hematoxylin and eosin, and von Kossa staining. Renal oxidative stress indexes including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), were analyzed. The renal expression of interleukin-1 beta (IL-1beta), gasdermin D (GSDMD), osteopontin (OPN), CD44, and monocyte chemotactic protein 1 (MCP-1), and EMT-related proteins in renal tubular epithelial cells was assessed. Cell viability and the apoptosis ratio were evaluated. RESULTS: In vivo, vitexin alleviated crystal deposition and kidney tissue injury, and decreased the level of MDA, and increased the levels of SOD, GSH, and CAT. Vitexin also reduced the levels of the pyroptosis-related proteins GSDMD, NLRP3, cleaved caspase-1, and mature IL-1beta, which were elevated in mice with nephrolithiasis, and repressed apoptosis and the expression of OPN and CD44. Moreover, vitexin mitigated F4/80-positive macrophage infiltration and MCP-1 expression in the kidneys. Furthermore, an in vitro study showed that vitexin increased the viability of HK-2 cells and THP-1-derived macrophages, which was impaired by treatment with COM crystals, decreased the medium lactate dehydrogenase (LDH) level, and inhibited the expression of pyroptosis-related proteins in HK-2 cells and macrophages. Vitexin repressed EMT of HK-2 cells, with increased expression of pan-cytokeratin (Pan-ck) and decreased expression of Vimentin and alpha-smooth muscle actin (alpha-SMA), and downregulated the Wnt/beta-catenin pathway. Moreover, vitexin suppressed tumor necrosis factor-alpha (TNF-alpha) and IL-1beta mRNA expression, which was upregulated by COM in macrophages. CONCLUSION: Vitexin exerts protective effects against nephrolithiasis by inhibiting pyroptosis activation, apoptosis, EMT, and macrophage infiltration. In addition, GSDMD-related pyroptosis mediates nephrolithiasis. CI - Copyright (c) 2021 Elsevier GmbH. All rights reserved. FAU - Ding, Tao AU - Ding T AD - Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai 200433, PR China. FAU - Zhao, Tingting AU - Zhao T AD - Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai 200433, PR China. FAU - Li, Yinhui AU - Li Y AD - Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai 200433, PR China. FAU - Liu, Zhixiao AU - Liu Z AD - Department of Histology and Embryology, Naval Medical University, Shanghai 200433, PR China. FAU - Ding, Jiarong AU - Ding J AD - Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai 200433, PR China. FAU - Ji, Boyao AU - Ji B AD - Department of Histology and Embryology, Naval Medical University, Shanghai 200433, PR China. FAU - Wang, Yue AU - Wang Y AD - Department of Histology and Embryology, Naval Medical University, Shanghai 200433, PR China; Shanghai Key Lab of Cell Engineering, Shanghai 200433, PR China. Electronic address: wangyuesmmu@163.com. FAU - Guo, Zhiyong AU - Guo Z AD - Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai 200433, PR China. Electronic address: drguozhiyong@163.com. LA - eng PT - Journal Article DEP - 20210329 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Glyoxylates) RN - 0 (Protective Agents) RN - 2612HC57YE (Calcium Oxalate) RN - 4Y8F71G49Q (Malondialdehyde) RN - 7V515PI7F6 (Apigenin) RN - 9VP70K75OK (vitexin) RN - JQ39C92HH6 (glyoxylic acid) SB - IM MH - Animals MH - Apigenin/*pharmacology MH - Apoptosis/drug effects MH - Calcium Oxalate/*metabolism/toxicity MH - Cell Line MH - Disease Models, Animal MH - Glyoxylates/toxicity MH - Humans MH - Kidney/*drug effects/pathology MH - Male MH - Malondialdehyde/metabolism MH - Mice, Inbred C57BL MH - Nephrolithiasis/chemically induced/drug therapy/prevention & control MH - Oxidative Stress/drug effects/physiology MH - Protective Agents/*pharmacology MH - Pyroptosis/*drug effects/physiology MH - Mice OTO - NOTNLM OT - Epithelial-mesenchymal transition OT - Gasdermin D OT - NLRP3 OT - Nephrolithiasis OT - Pyroptosis OT - Vitexin EDAT- 2021/04/16 06:00 MHDA- 2021/06/03 06:00 CRDT- 2021/04/15 20:25 PHST- 2020/12/14 00:00 [received] PHST- 2021/03/01 00:00 [revised] PHST- 2021/03/25 00:00 [accepted] PHST- 2021/04/16 06:00 [pubmed] PHST- 2021/06/03 06:00 [medline] PHST- 2021/04/15 20:25 [entrez] AID - S0944-7113(21)00104-5 [pii] AID - 10.1016/j.phymed.2021.153562 [doi] PST - ppublish SO - Phytomedicine. 2021 Jun;86:153562. doi: 10.1016/j.phymed.2021.153562. Epub 2021 Mar 29.