Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone
Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone
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DOI：
10.2337/db05-1683
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发表时间：
2006-10-01
期刊：
影响因子：
7.7
通讯作者：
Suga, Shin-ichi
中科院分区：
文献类型：
--
作者：
Makino, Hisashi;Miyamoto, Yoshihiro;Suga, Shin-ichi
肾小球损伤在糖尿病肾病的发生发展中起着关键作用。为了阐明糖尿病性肾小球病变的分子机制，我们使用cDNA微阵列比较了db/db小鼠与db/m对照小鼠在正常白蛋白尿阶段（以高血糖为特征）和糖尿病性肾病早期（伴白蛋白尿升高）的肾小球基因表达谱。在正常白蛋白尿阶段的db/db小鼠中，在肾小球形成中起关键作用的缺氧诱导因子-let（HIF-1 α）、肝配蛋白B2、肾小球上皮蛋白1和Pod-1已经与葡萄糖代谢、脂质代谢和氧化应激相关基因的改变平行上调。足细胞结构相关基因，辅肌动蛋白4 α和肌营养不良蛋白聚糖1（DG 1），也显着上调在早期阶段。通过定量RT-PCR证实了这些基因表达的改变。通过吡格列酮治疗，肝配蛋白B2、POD-1、辅肌动蛋白4a和DG 1的基因表达以及氧化应激和脂质代谢的基因表达随着蛋白尿的减轻而恢复。此外，吡格列酮可部分减弱HIF-1 α蛋白表达。这些结果表明，不仅代谢改变和氧化应激，而且与肾小球和足细胞结构相关的基因表达的改变，可能参与2型糖尿病早期糖尿病肾小球病变的发病机制。
Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-let (HIF-1 alpha), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4 alpha and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4a, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1 alpha protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes.