Molecular mechanisms of proximal tubule cell endocytosis and its pathological roles in the development of chronic kidney disease

我们分析了近端小管细胞中的内源性受体megalin的功能的分子机制。我们还建立了一种新的与巨蛋白相关的方法来评估慢性肾脏疾病，并探讨了巨蛋白介导的慢性肾脏疾病的发生机制。1)我们发现巨蛋白和非肌型肌球蛋白重链IIA与近端小管细胞中的接头蛋白失活-2相互作用(Kidney Int 2009)。2)2型糖尿病和代谢综合征患者的血清内毒素水平升高。我们发现，通过内毒素-肿瘤坏死因子-α-ERK1/2信号通路，巨蛋白在近端肾小管细胞中表达下调(BBRC2011)。3)我们建立了检测人巨蛋白的酶联免疫吸附试验体系，发现尿巨蛋白排泄是糖尿病肾病早期诊断和评估严重程度以及分析心血管风险的有用生物标志物(糖尿病护理2012)。4)我们发现肝源性血管紧张素原参与肾脏肾素-血管紧张素系统的激活(血管紧张素II的产生)，肾小球过滤的血管紧张素原被近端肾小管细胞摄取(JASN 2012)。

We analyzed molecular mechanisms of functions of megalin, an endocytic receptor in proximal tubule cells. We also established a novel megalin-related method for evaluating chronic kidney disease and investigated megalin-mediated mechanisms of the development of chronic kidney disease.1) We found that megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells(Kidney Int 2009).2) Endotoxins are increased in the serum of patients with type 2 diabetes and metabolic syndrome. We found that megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells(BBRC 2011).3) We established ELISA systems to measure human megalin and showed that urinary megalin excretion is a useful biomarker for early diagnosis and evaluation of the severity of diabetic nephropathy and for analyzing cardiovascular risks(Diabetes Care 2012).4) We found that liver-derived angiotensinogen is involved in the activation of the renin-angiotensin system(generation of angiotensin II) in the kidney and that glomerular-filtered angiotensinogen is taken up by megalin in proximal tubule cells(JASN 2012).