PMID- 33994251 OWN - NLM STAT- MEDLINE DCOM- 20210630 LR - 20210630 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 87 DP - 2021 Jul TI - Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-beta/SMAD3 signaling. PG - 153552 LID - S0944-7113(21)00094-5 [pii] LID - 10.1016/j.phymed.2021.153552 [doi] AB - BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (alpha-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-beta (TGF-beta) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-beta signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy. CI - Copyright (c) 2021. Published by Elsevier GmbH. FAU - Ren, Qian AU - Ren Q AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Tao, Sibei AU - Tao S AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Guo, Fan AU - Guo F AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Wang, Bo AU - Wang B AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Yang, Letian AU - Yang L AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Ma, Liang AU - Ma L AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. Electronic address: liang_m@scu.edu.cn. FAU - Fu, Ping AU - Fu P AD - Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China. LA - eng PT - Journal Article DEP - 20210322 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Flavonols) RN - 0 (Interleukin-6) RN - 0 (STAT3 Transcription Factor) RN - 0 (Smad3 Protein) RN - 0 (Smad3 protein, mouse) RN - 0 (Stat3 protein, mouse) RN - 0 (Transforming Growth Factor beta) RN - 268B43MJ25 (Uric Acid) RN - EC 2.7.10.2 (Jak2 protein, mouse) RN - EC 2.7.10.2 (Janus Kinase 2) RN - OO2ABO9578 (fisetin) SB - IM MH - Administration, Oral MH - Animals MH - Fibrosis MH - Flavonols/administration & dosage/*pharmacology/therapeutic use MH - Gene Expression Regulation/drug effects MH - Hyperuricemia/*drug therapy/pathology MH - Interleukin-6/antagonists & inhibitors/genetics/*metabolism MH - Janus Kinase 2/antagonists & inhibitors/genetics/metabolism MH - Kidney/drug effects/pathology MH - Kidney Diseases/blood/*drug therapy/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - STAT3 Transcription Factor/antagonists & inhibitors/genetics/metabolism MH - Smad3 Protein/genetics/metabolism MH - Transforming Growth Factor beta/genetics/*metabolism MH - Uric Acid/blood/urine OTO - NOTNLM OT - Fisetin OT - Hyperuricemic nephropathy OT - Inflammation OT - Kidney fibrosis OT - Uric acid EDAT- 2021/05/18 06:00 MHDA- 2021/07/01 06:00 CRDT- 2021/05/17 05:48 PHST- 2021/01/05 00:00 [received] PHST- 2021/03/11 00:00 [revised] PHST- 2021/03/14 00:00 [accepted] PHST- 2021/05/18 06:00 [pubmed] PHST- 2021/07/01 06:00 [medline] PHST- 2021/05/17 05:48 [entrez] AID - S0944-7113(21)00094-5 [pii] AID - 10.1016/j.phymed.2021.153552 [doi] PST - ppublish SO - Phytomedicine. 2021 Jul;87:153552. doi: 10.1016/j.phymed.2021.153552. Epub 2021 Mar 22.