FGF23不依赖Klotho而促进心肾综合征小鼠肾脏纤维化

发布时间：2018-05-02 12:08

  本文选题：FGF23 + 心肌梗死　； 参考：《南方医科大学》2017年博士论文

【摘要】：背景与目的:众所周知,心肾综合征具有很高的死亡率,但是其病理机制仍不清楚。成纤维细胞生长因子(Fibroblast growth factor 23,FGF23)是一个新发现的内分泌激素,由骨细胞/成骨细胞产生,主要作用于肾脏和甲状旁腺,通过与其受体(FGFR)和共受体Klotho的结合,增加尿磷排泄,进而调节血磷平衡及维生素D代谢。最新研究表明心功能紊乱和肾功能紊乱都可上调血清FGF23水平,FGF23以Klotho非依赖的方式与FGFR4结合,进而通过激活calcineurin/NFAT信号通路促进心肌肥厚和纤维化,FGF23的缺失可以导致生长抑制和寿命的缩短。FGF23过表达是否促进心肾综合征的发展,目前仍不清楚。研究目的:探讨FGF23对心肌梗死诱导的心肾综合征小鼠肾脏纤维化的影响。研究方法:通过心肌梗死6周的方法来制备心肾综合征小鼠模型。通过心肌内注射FGF23腺相关病毒(AAV-FGF23)和连续腹腔注射FGF23受体抑制剂PD173074的方法来观察FGF23对心肾功能紊乱、肾脏纤维化以及纤维化相关信号通路的影响。用FGF23重组蛋白刺激正常大鼠成纤维细胞(NRK-49F)24小时,通过实时定量PCR和Western blot来观察FGF23对NRK-49F细胞纤维化相关基因和蛋白的影响。研究结果:心肾综合征小鼠可以显著增加血浆和肾脏FGF23的表达水平,上调肾脏FGFR4,β-catenin,TGF-β,Ⅰ型胶原和Vimentin的表达,下调肾脏Klotho的表达,并诱导心肾功能紊乱和心肾纤维化。心肌内过表达FGF23腺相关病毒将加重这些变化,FGF23受体抑制剂PD173074腹腔连续注射2周可抑制这些变化。在培养的NRK-49F细胞中可检测到FGFR4的表达,但是未检测到Klotho的表达。FGF23重组蛋白不仅促进NRK-49F细胞的增殖,而且上调纤维化相关蛋白β-catenin,TGF-β,Ⅰ 型胶原和 Vimentin 的表达。研究结论:FGF23以Klotho非依赖的方式促进心肾综合征小鼠肾脏纤维化。
[Abstract]:Background & objective: it is well known that cardiorenal syndrome has a high mortality rate, but its pathological mechanism remains unclear. Fibroblast growth factor 23 (FGF23) is a newly discovered endocrine hormone produced by osteoblasts / osteoblasts. It acts mainly on the kidney and parathyroid gland and increases urinary phosphorus excretion by binding to its receptor FGFR) and co-receptor Klotho. Then regulate blood phosphorus balance and vitamin D metabolism. Recent studies have shown that both cardiac dysfunction and renal dysfunction can up-regulate serum FGF23 levels. FGF23 binds to FGFR4 in a Klotho independent manner. Furthermore, it is not clear whether the activation of calcineurin/NFAT signaling pathway can promote myocardial hypertrophy and the absence of fibrotic FGF23, which can result in growth inhibition and shortening of life span. Whether the overexpression of FGF23 can promote the development of cardiorenal syndrome is still unclear. Objective: to investigate the effect of FGF23 on renal fibrosis induced by myocardial infarction in mice with cardiorenal syndrome. Methods: the model of cardiorenal syndrome was established by myocardial infarction for 6 weeks. The effects of FGF23 adeno-associated virus (AAV-FGF23) and continuous intraperitoneal injection of FGF23 receptor inhibitor (PD173074) on cardiorenal dysfunction, renal fibrosis and fibrosis-related signaling pathway were observed by intramyocardial injection of AAV-FGF23 and continuous intraperitoneal injection of FGF23 receptor inhibitor PD173074. Normal rat fibroblasts were stimulated with FGF23 recombinant protein for 24 hours. The effects of FGF23 on NRK-49F fibrosis related genes and proteins were observed by real-time quantitative PCR and Western blot. Results: in mice with cardiorenal syndrome, the expression of FGF23 in plasma and kidney was significantly increased, the expression of FGFR4, 尾 -cateninine TGF- 尾, type 鈪，

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