Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.
Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.
复制标题
DOI：
10.1038/srep28882
复制
发表时间：
2016-06-29
影响因子：
4.6
通讯作者：
Higaki J
中科院分区：
文献类型：
--
作者：
Pei Z;Okura T;Nagao T;Enomoto D;Kukida M;Tanino A;Miyoshi K;Kurata M;Higaki J
高胆固醇血症是肾脏损伤的一个公认的危险因素，可导致慢性肾脏疾病（CKD）。骨桥蛋白（OPN）与几种肾脏疾病的病理有关。本研究旨在评价OPN对高胆固醇血症所致肾功能障碍的影响。8周龄雄性小鼠分为4组：载脂蛋白E敲除（ApoE−/−）和ApoE/OPN敲除（ApoE−/−/OPN−/−）小鼠，分别饲喂正常饮食（ND）和高胆固醇饮食（HD）。4周后，周期性酸-希夫（PAS）和油红O染色显示ApoE−/−HD小鼠肾小球中有过量的脂质沉积，而ApoE−/−/OPN−/−HD小鼠肾小球中有明显的脂质沉积。凝集素样氧化低密度脂蛋白受体-1 （LOX-1）在ApoE−/−/OPN−/−HD小鼠肾小球中的表达低于ApoE−/−HD小鼠。体外实验中，原代系膜细胞与重组小鼠OPN （rmOPN）孵育。RmOPN诱导原代系膜细胞LOX-1 mRNA和蛋白表达。ERK抑制剂预处理可抑制rmOPN诱导的LOX-1基因表达。这些结果表明，OPN有助于高胆固醇血症的肾脏损害，并提示抑制OPN可能为预防高胆固醇血症提供潜在的治疗靶点。
Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE−/−) and ApoE/OPN knockout (ApoE−/−/OPN−/−) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE−/−HD mice, however, significantly suppressed in ApoE−/−/OPN−/−HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE−/−/OPN−/−HD mice than ApoE−/−HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia.