Kang Min-Kyung, Park Sin-Hye, Kim Yun-Ho, Lee Eun-Jung, Antika Lucia Dwi, Kim Dong Yeon, Choi Yean-Jung, Kang Young-Hee
Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
Acta Pharmacol Sin. 2017 Aug;38(8):1129-1140. doi: 10.1038/aps.2017.30. Epub 2017 May 15.
Glomerular epithelial podocytes are highly specialized cells that play a crucial role in maintaining normal function of the glomerular filtration barrier via their foot processes. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid found in propolis and mushrooms that has anti-inflammatory, antioxidant and anticancer properties. This study aimed to evaluate the renoprotective effects of chrysin on podocyte apoptotic loss and slit diaphragm protein deficiency in high glucose-exposed podocytes and in db/db mouse kidneys. Exposure to high glucose (33 mmol/L) caused glomerular podocyte apoptosis in vitro, which was dose-dependently attenuated by nontoxic chrysin (1-20 μmol/L) through reduction of DNA fragmentation. Chrysin treatment dose-dependently restored the increased Bax/Bcl-2 ratio, and suppressed Apaf-1 induction and the elevated cytochrome c release in high glucose-exposed renal podocytes. In diabetic db/db mice, oral administration of chrysin (10 mg·kg·d, for 10 weeks) significantly attenuated proteinuria, and alleviated the abnormal alterations in glomerular ultrastructure, characterized by apoptotic podocytes and foot process effacement. In addition, this compound improved the induction of slit diaphragm proteins podocin/nephrin in the diabetic glomeruli. Exposure to high glucose elevated the unfolded protein response (UPR) to ER stress in renal podocytes, evidenced by up-regulation of PERK-eIF2α-ATF4-CHOP. Chrysin treatment blocked such ER stress responses pertinent to podocyte apoptosis and reduced synthesis of slit diaphragm proteins in vitro and in vivo. These observations demonstrate that targeting ER stress is an underlying mechanism of chrysin-mediated amelioration of diabetes-associated podocyte injury and dysfunction.
肾小球上皮足细胞是高度特化的细胞，通过其足突在维持肾小球滤过屏障的正常功能中发挥关键作用。白杨素（5,7 - 二羟基黄酮）是一种存在于蜂胶和蘑菇中的天然黄酮类化合物，具有抗炎、抗氧化和抗癌特性。本研究旨在评估白杨素对高糖暴露的足细胞以及db/db小鼠肾脏中足细胞凋亡性损失和裂孔隔膜蛋白缺乏的肾脏保护作用。体外暴露于高糖（33 mmol/L）会导致肾小球足细胞凋亡，无毒的白杨素（1 - 20 μmol/L）通过减少DNA片段化以剂量依赖性方式减弱这种凋亡。白杨素处理以剂量依赖性方式恢复了高糖暴露的肾足细胞中升高的Bax/Bcl - 2比率，并抑制了Apaf - 1的诱导以及细胞色素c释放的增加。在糖尿病db/db小鼠中，口服白杨素（10 mg·kg·d，持续10周）可显著减轻蛋白尿，并减轻以凋亡足细胞和足突消失为特征的肾小球超微结构异常改变。此外，该化合物改善了糖尿病肾小球中裂孔隔膜蛋白podocin/nephrin的诱导。暴露于高糖会使肾足细胞中内质网应激的未折叠蛋白反应（UPR）升高，这通过PERK - eIF2α - ATF4 - CHOP的上调得以证明。白杨素处理可阻断与足细胞凋亡相关的内质网应激反应，并在体外和体内减少裂孔隔膜蛋白的合成。这些观察结果表明，靶向内质网应激是白杨素介导改善糖尿病相关足细胞损伤和功能障碍的潜在机制。
