Epithelial-Mesenchymal Transition as a Potential Explanation for Podocyte Depletion in Diabetic Nephropathy
Epithelial-Mesenchymal Transition as a Potential Explanation for Podocyte Depletion in Diabetic Nephropathy
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DOI：
10.1053/j.ajkd.2009.05.009
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发表时间：
2009-10-01
影响因子：
13.2
通讯作者：
Saito, Yoshihiko
中科院分区：
文献类型：
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作者：
Yamaguchi, Yukinari;Iwano, Masayuki;Saito, Yoshihiko
背景：肾小球足细胞耗竭是进展性糖尿病肾病的重要特征。尽管最合理的解释是细胞凋亡后足细胞从肾小球基底膜脱离，但其机制尚不清楚。成纤维细胞特异性蛋白1(FSP1；研究设计：回顾性横断面分析。背景与对象：109例2型糖尿病患者，其中43例(39%)接受了肾脏活检。预测因素：糖尿病肾病的临床分期(4类)和组织学分级(5类)。结果：FSP1在肾活检标本的尿液和肾小球足细胞中表达。测量：免疫组织化学、实时定量聚合酶链式反应、免疫组织化学、实时定量聚合酶链式反应、结果：109例患者中尿蛋白正常38例(35%)，微量蛋白尿16例(15%)，大量蛋白尿8例(7%)，肾功能减退47例(43%)。尿沉渣中约95%的足细胞未发生凋亡，86%的足细胞表达FSP1。大量白蛋白尿组尿沉渣中FSP1阳性足细胞数明显多于正常白蛋白尿组(P=0.03)。糖尿病患者肾小球内FSP1表达几乎仅见于足细胞，弥漫性系膜病变组肾小球FSP1阳性足细胞数明显多于局灶性系膜病变组(P=0.01)。在有结节病变的肾小球中，这一数字也高于无结节病变的肾小球(P<；0.001)。FSP1阳性的足细胞选择性地表达Snaill和整合素连接的激酶，这是一种已知的上皮-间充质转化的触发因素。限制：没有代表性的研究群体。结论：这些结果表明，糖尿病患者足细胞中FSPi的出现与糖尿病肾病更严重的临床和病理结果有关，可能是由于通过上皮-间充质转化样现象诱导足细胞分离。Am J肾脏Dis 54：653-664。2009年由国家肾脏基金会，Inc.
Background: Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition.Study Design: Retrospective cross-sectional analysis.Settings & Participants: 109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy.Predictor: Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy.Outcome: FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens.Measurements: Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization.Results: 38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria (P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy (P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions (P < 0.001). FSP1-positive podocytes selectively expressed Snaill and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition.Limitations: Nonrepresentative study population.Conclusions: These results suggest that the appearance of FSPi in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition-like phenomena. Am J Kidney Dis 54:653-664. 2009 by the National Kidney Foundation, Inc.