Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition
Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition
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DOI：
10.1007/s00109-015-1301-3
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发表时间：
2015-07-01
影响因子：
4.7
通讯作者：
Kang, Young-Hee
中科院分区：
文献类型：
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作者：
Kang, Min-Kyung;Park, Sin-Hye;Kang, Young-Hee
肾纤维化是糖尿病肾病（DN）发病机制中的一个关键事件。上皮间质转化（EMT）的过程有助于基质蛋白在肾脏中的积累，其中肾小管上皮细胞在进行性肾纤维化中发挥重要作用。目前的研究调查了蜂胶和草药中存在的白杨素（5,7-二羟基黄酮）可抑制慢性高血糖引起的肾小管 EMT 和肾小管间质纤维化。将人肾近端肾小管上皮细胞 (RPTEC) 在含有 5.5 mM 葡萄糖、27.5 mM 甘露醇（作为渗透压对照）或 33 mM 葡萄糖 (HG) 的培养基中在不存在和存在 1-20 muM 白杨素的情况下孵育 72 小时。白杨素通过阻断 RPTEC 和 db/db 小鼠中间质标记物波形蛋白、α-平滑肌肌动蛋白和成纤维细胞特异性蛋白 1 的表达，显着抑制高糖诱导的肾 EMT。白杨素逆转了 RPTEC 中 HG 诱导的上皮标记物 E-钙粘蛋白的下调和 HG 增强的 N-钙粘蛋白的诱导。此外，白杨素还能抑制肾小管细胞中IV型胶原蛋白的产生以及小鼠肾脏中胶原纤维的沉积。此外，白杨素阻断肾小管细胞迁移，同时降低基质金属蛋白酶-2活性，表明上皮细胞紊乱和肾小管基底膜破坏。白杨素恢复了糖尿病小鼠中下调的紧密连接蛋白 Zona occlusionns 蛋白-1 (ZO-1) 和 occludin 的诱导。白杨素抑制慢性高血糖引起的肾小管 EMT 介导的肾小管间质纤维化。因此，白杨素可能是治疗肾纤维化相关 DN 的有效肾脏保护剂。
Renal fibrosis is a crucial event in the pathogenesis of diabetic nephropathy (DN). The process known as epithelial to mesenchymal transition (EMT) contributes to the accumulation of matrix proteins in kidneys, in which renal tubular epithelial cells play an important role in progressive renal fibrosis. The current study investigated that chrysin (5,7-dihydroxyflavone) present in bee propolis and herbs, inhibited renal tubular EMT and tubulointerstitial fibrosis due to chronic hyperglycemia. Human renal proximal tubular epithelial cells (RPTEC) were incubated in media containing 5.5 mM glucose, 27.5 mM mannitol (as an osmotic control), or 33 mM glucose (HG) in the absence and presence of 1-20 mu M chrysin for 72 h. Chrysin significantly inhibited high glucose-induced renal EMT through blocking expression of the mesenchymal markers vimentin, alpha-smooth muscle actin, and fibroblast-specific protein-1 in RPTEC and db/db mice. Chrysin reversed the HG-induced down-regulation of the epithelial marker E-cadherin and the HG-enhanced N-cadherin induction in RPTEC. In addition, chrysin inhibited the production of collagen IV in tubular cells and the deposition of collagen fibers in mouse kidneys. Furthermore, chrysin blocked tubular cell migration concurrent with decreasing matrix metalloproteinase-2 activity, indicating epithelial cell derangement and tubular basement membrane disruption. Chrysin restored the induction of the tight junction proteins Zona occludens protein-1 (ZO-1) and occludin downregulated in diabetic mice. Chrysin inhibited renal tubular EMT-mediated tubulointerstitial fibrosis caused by chronic hyperglycemia. Therefore, chrysin may be a potent renoprotective agent for the treatment of renal fibrosis-associated DN.