本文選題：FGF23 + 心肌梗死��； 參考：《南方醫(yī)科大學》2017年博士論文

【摘要】：背景與目的:眾所周知,心腎綜合征具有很高的死亡率,但是其病理機制仍不清楚。成纖維細胞生長因子(Fibroblast growth factor 23,FGF23)是一個新發(fā)現(xiàn)的內(nèi)分泌激素,由骨細胞/成骨細胞產(chǎn)生,主要作用于腎臟和甲狀旁腺,通過與其受體(FGFR)和共受體Klotho的結(jié)合,增加尿磷排泄,進而調(diào)節(jié)血磷平衡及維生素D代謝。最新研究表明心功能紊亂和腎功能紊亂都可上調(diào)血清FGF23水平,FGF23以Klotho非依賴的方式與FGFR4結(jié)合,進而通過激活calcineurin/NFAT信號通路促進心肌肥厚和纖維化,FGF23的缺失可以導致生長抑制和壽命的縮短。FGF23過表達是否促進心腎綜合征的發(fā)展,目前仍不清楚。研究目的:探討FGF23對心肌梗死誘導的心腎綜合征小鼠腎臟纖維化的影響。研究方法:通過心肌梗死6周的方法來制備心腎綜合征小鼠模型。通過心肌內(nèi)注射FGF23腺相關病毒(AAV-FGF23)和連續(xù)腹腔注射FGF23受體抑制劑PD173074的方法來觀察FGF23對心腎功能紊亂、腎臟纖維化以及纖維化相關信號通路的影響。用FGF23重組蛋白刺激正常大鼠成纖維細胞(NRK-49F)24小時,通過實時定量PCR和Western blot來觀察FGF23對NRK-49F細胞纖維化相關基因和蛋白的影響。研究結(jié)果:心腎綜合征小鼠可以顯著增加血漿和腎臟FGF23的表達水平,上調(diào)腎臟FGFR4,β-catenin,TGF-β,Ⅰ型膠原和Vimentin的表達,下調(diào)腎臟Klotho的表達,并誘導心腎功能紊亂和心腎纖維化。心肌內(nèi)過表達FGF23腺相關病毒將加重這些變化,FGF23受體抑制劑PD173074腹腔連續(xù)注射2周可抑制這些變化。在培養(yǎng)的NRK-49F細胞中可檢測到FGFR4的表達,但是未檢測到Klotho的表達。FGF23重組蛋白不僅促進NRK-49F細胞的增殖,而且上調(diào)纖維化相關蛋白β-catenin,TGF-β,Ⅰ 型膠原和 Vimentin 的表達。研究結(jié)論:FGF23以Klotho非依賴的方式促進心腎綜合征小鼠腎臟纖維化。
[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，

本文編號：1833835