Kang Min-Kyung, Park Sin-Hye, Choi Yean-Jung, Shin Daekeun, Kang Young-Hee
Department of Food and Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702, Republic of Korea.
J Mol Med (Berl). 2015 Jul;93(7):759-72. doi: 10.1007/s00109-015-1301-3. Epub 2015 Jun 11.
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 μM chrysin for 72 h. Chrysin significantly inhibited high glucose-induced renal EMT through blocking expression of the mesenchymal markers vimentin, α-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.
• Glucose increases renal tubular epithelial induction of vimentin, α-SMA and FSP-1. • Glucose enhances renal EMT by blocking tubular epithelial E-cadherin expression. • Chrysin inhibits tubular EMT-mediated tubulointerstitial fibrosis in mouse kidneys. • Chrysin restores renal tubular induction of ZO-1 and occludin downregulated in diabetic mice. • Chrysin blocks glucose-induced renal tubular cell migration with reducing MMP-2 activity.
肾纤维化是糖尿病肾病（DN）发病机制中的关键事件。上皮-间质转化（EMT）过程导致肾脏中基质蛋白的积累，其中肾小管上皮细胞在进行性肾纤维化中起重要作用。本研究调查了蜂胶和草药中含有的白杨素（5,7-二羟基黄酮）可抑制由于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（作为渗透对照）或33 mM葡萄糖（高糖，HG）的培养基中培养，在有无1-20 μM白杨素的情况下培养72小时。白杨素通过阻断RPTEC和db/db小鼠中间质标志物波形蛋白、α-平滑肌肌动蛋白和成纤维细胞特异性蛋白-1的表达，显著抑制高糖诱导的肾EMT。白杨素逆转了高糖诱导的RPTEC中上皮标志物E-钙黏蛋白的下调以及高糖增强的N-钙黏蛋白的诱导。此外，白杨素抑制肾小管细胞中IV型胶原的产生以及小鼠肾脏中胶原纤维的沉积。此外，白杨素在降低基质金属蛋白酶-2活性的同时阻断肾小管细胞迁移，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紧密连接蛋白闭合蛋白-1（ZO-1）和闭合蛋白下调的诱导。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，白杨素可能是治疗与肾纤维化相关的糖尿病肾病的有效肾脏保护剂。
• 葡萄糖增加肾小管上皮细胞中波形蛋白、α-SMA和FSP-1的诱导。
• 葡萄糖通过阻断肾小管上皮E-钙黏蛋白的表达增强肾EMT。
• 白杨素抑制小鼠肾脏中肾小管EMT介导的肾小管间质纤维化。
• 白杨素恢复糖尿病小鼠中肾小管对ZO-1和闭合蛋白下调的诱导。
• 白杨素通过降低MMP-2活性阻断葡萄糖诱导的肾小管细胞迁移。
