Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts
Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts
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DOI：
10.1152/ajprenal.90352.2008
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发表时间：
2009-06-01
影响因子：
4.2
通讯作者：
Strutz, Frank
中科院分区：
文献类型：
--
作者：
Vasko, Radovan;Koziolek, Michael;Strutz, Frank
2005年10月27日，李文辉.碱性成纤维细胞生长因子（FGF-2）在糖尿病肾病中的作用及高血糖对人肾成纤维细胞的诱导机制美国肾脏生理学杂志296：F1452-F1463，2009年。首次发表于2009年3月11日; doi：10.1152/ajprenal.90352.2008。碱性成纤维细胞生长因子（FGF-2）在肾纤维化中发挥作用，但其在糖尿病肾病肾小管间质受累中的潜在意义尚不清楚。我们评估了FGF-2在糖尿病肾病患者肾活检组织中的表达，并研究了其在高血糖条件下在人肾成纤维细胞中的诱导机制。与对照组相比，糖尿病肾病肾小管间质FGF-2表达显著上调，与损伤程度有良好的相关性。与正常葡萄糖相比，高糖培养的成纤维细胞显示FGF-2 mRNA以及蛋白质合成和分泌增加。高血糖下的增殖率显着更高，可以通过添加中和FGF-2抗体几乎完全抑制。增殖的改变与p27（kip1）表达的变化相关。高血压诱导PKC-β 1和PKC-β 2的表达;然而，仅抑制PKC-β 1而非PKC-β 2导致FGF-2水平显著降低。通过FGF-2和PKC-β在体内人糖尿病肾脏中的共定位证实了培养结果和功能关联的相关性。高葡萄糖刺激纤维连接蛋白的合成和分泌，这可以通过抑制PKC-β 1和在较小程度上通过抑制FGF-2来基本上阻止。在高血糖下，p38丝裂原活化蛋白激酶的活性磷酸化形式的表达上调;然而，其抑制对FGF-2的合成没有影响。我们的研究结果暗示FGF-2在糖尿病肾病发病机制中的高糖改变分子信号传导中的作用。
Vasko R, Koziolek M, Ikehata M, Rastaldi MP, Jung K, Schmid H, Kretzler M, Muller GA, Strutz F. Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts. Am J Physiol Renal Physiol 296: F1452-F1463, 2009. First published March 11, 2009; doi: 10.1152/ajprenal.90352.2008.-Basic fibroblast growth factor (FGF-2) plays a role in renal fibrogenesis, although its potential implications for tubulointerstitial involvement in diabetic nephropathy are unknown. We evaluated the expression of FGF-2 in kidney biopsies from patients with diabetic nephropathy and studied the mechanisms of its induction in human renal fibroblasts under hyperglycemia. Tubulointerstitial expression of FGF-2 was significantly upregulated in diabetic nephropathy compared with control kidneys with a good correlation to the degree of the injury. Fibroblasts cultivated in high glucose displayed increased FGF-2 mRNA as well as protein synthesis and secretion compared with normal glucose. Proliferation rates under hyperglycemia were significantly higher and could be almost completely inhibited by addition of a neutralizing FGF-2 antibody. Alterations in proliferation were associated with changes in p27(kip1) expression. Hyperglycemia induced the expression of PKC-beta 1 and PKC-beta 2; however, only inhibition of PKC-beta 1 but not PKC-beta 2 led to a significant decrease of FGF-2 levels. Relevance of the culture findings and functional association was corroborated by colocalization of FGF-2 and PKC-beta in human diabetic kidneys in vivo. High glucose stimulated fibronectin synthesis and secretion, which could be substantially prevented by inhibition of PKC-beta 1 and to a lesser extent by inhibiting the FGF-2. Expression of active phosphorylated form of p38 mitogen-activated protein kinase was upregulated under hyperglycemia; however, its inhibition had no effects on FGF-2 synthesis. Our results implicate a role of FGF-2 in high glucose-altered molecular signaling in pathogenesis of diabetic renal disease.