Yamaguchi Yukinari, Iwano Masayuki, Suzuki Daisuke, Nakatani Kimihiko, Kimura Kuniko, Harada Koji, Kubo Atsushi, Akai Yasuhiro, Toyoda Masao, Kanauchi Masao, Neilson Eric G, Saito Yoshihiko
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Am J Kidney Dis. 2009 Oct;54(4):653-64. doi: 10.1053/j.ajkd.2009.05.009. Epub 2009 Jul 17.
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.
Retrospective cross-sectional analysis.
SETTINGS & PARTICIPANTS: 109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy.
Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy.
FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens.
Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization.
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 Snail1 and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition.
Nonrepresentative study population.
These results suggest that the appearance of FSP1 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.
肾小球足细胞耗竭是进行性糖尿病肾病的一个重要特征。尽管对于这种足细胞耗竭最合理的解释是细胞凋亡后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；由S100A4基因编码）是S100钙结合蛋白家族的成员，在组织成纤维细胞或通过上皮-间质转化转变为成纤维细胞的上皮细胞的细胞质中组成性表达。
回顾性横断面分析。
109例2型糖尿病患者，其中43例（39%）接受了肾活检。
糖尿病肾病的临床分期（4类）和组织学分级（5类）。
尿和肾活检标本肾小球中足细胞的FSP1表达。
免疫组织化学、实时聚合酶链反应和原位杂交。
109例患者中38例（35%）为正常白蛋白尿，16例（15%）为微量白蛋白尿，8例（7%）为大量白蛋白尿，47例（43%）肾功能减退。尿沉渣中约95%的足细胞未凋亡，86%表达FSP1。大量白蛋白尿患者尿沉渣中FSP1阳性足细胞数量显著多于正常白蛋白尿患者（P = 0.03）。FSP1在肾小球内的表达几乎仅发生在糖尿病患者的足细胞中，显示弥漫性系膜病变的肾小球中FSP1阳性足细胞数量多于显示局灶性系膜病变的肾小球（P = 0.01）。有结节性病变的肾小球中的数量也多于无结节性病变的肾小球（P < 0.001）。FSP1阳性足细胞选择性表达Snail1和整合素连接激酶，这是上皮-间质转化的已知触发因素。
非代表性研究人群。
这些结果表明，糖尿病患者足细胞中FSP1的出现与糖尿病肾病更严重的临床和病理表现相关，可能是因为通过上皮-间质转化样现象诱导足细胞脱离。
