Molecular mechanism of glomerular hyperfiltration in diabetic nephropathy revealed by gene expression profiling.

背景资料。为阐明糖尿病肾病的分子机制，采用高密度DNA芯片技术，对链脲佐菌素诱导的糖尿病CD-1(ICR)小鼠肾脏基因表达谱进行了研究。10周龄CD-1雄性小鼠随机分为4组：(1)对照组；(2)单侧肾切除(UX)组；(3)STZ糖尿病(STZ)组；(4)STZ-UX组。诱导后24周取材进行病理组织学检查。用基因发现阵列(GDA)比较对照组和STZ小鼠的基因表达谱。UX组小鼠肾小球明显肥大，系膜基质积聚较少。STZ和STZ+UX小鼠均有明显的肾小球肥大和肾小球硬化，肾切除对肾损伤无明显影响。通过在对照组和STZ小鼠之间的比较，发现了16个随着糖尿病诱导而表达增加的克隆和65个在糖尿病肾脏中表达降低的克隆。这37个已知基因与糖脂代谢、离子转运、转录因子、信号分子和细胞外基质相关分子有关。已知在不同组织中参与细胞分化和器官发生的基因UNC-18同源物、POU结构域转录因子2、疯狂边缘基因同源物、纤维鞘成分1、SOX-17、纤维蛋白2和MRJ在糖尿病肾脏早期存在差异表达。高血糖是STZ诱导的糖尿病CD-1小鼠肾小球硬化的主要决定因素，糖尿病肾脏早期基因表达改变可能在糖尿病肾病的发生发展中起关键作用。

Background. To elucidate molecular mechanism of diabetic nephropathy, high density DNA filter array was employed for the survey of gene expression profile of streptozotocin-induced diabetic CD-1 (ICR) mice kidney.Methods. Ten-week-old CD-1 male mice were divided into four groups (1) control, (2) unilaterally nephretomized (UX) mice, (3) STZ-induced diabetic (STZ) mice, and (4) STZ mice with unilateral renal ablation (STZ-UX). The pathological changes were examined at 24 weeks after the induction. The gene expression profile was compared between the control and STZ mice by Gene Discovery Array (GDA).Results. The glomeruli in UX mouse kidney showed prominent glomerular hypertrophy, while the accumulation of mesangial matrix was minimal. Both STZ and STZ + UX mice had significant glomerular hypertrophy and glomerulosclerosis and lesions were not enhanced by renal ablation. By comparison between control and STZ mice, 16 clones that increased in expression with the induction of diabetes and 65 clones that decreased in diabetic kidneys were identified. The 37 known genes were related to glucose and lipid metabolism, ion transport, transcription factors, signaling molecules and extracellular matrix-related molecules. The genes known to be involved in cell differentiation and organogenesis in various tissues, i.e. Unc-18 homologue, POU domain transcription factor 2, lunatic fringe gene homolog, fibrous sheath component 1, Sox-17, fibulin 2, and MRJ, were found to be differentially expressed in early phase of diabetic kidneys.Conclusions. Hyperglycemia was major determinant of glomerulosclerosis in STZ-induced diabetic CD-1 mice and the altered gene expression in the early phase of diabetic kidney may be critical for the development of diabetic nephropathy.