Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis.
Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis.
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通过微阵列分析确定，长期罗格列酮治疗可使肥胖 Zucker 大鼠肾脏中 ACE1、SCD1 和其他基因的表达正常化。
DOI：
10.1055/s-2008-1042429
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Ecelbarger,CM
中科院分区：
文献类型：
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作者：
Song,J;Liu,H;Ressom,HW;Tiwari,S;Ecelbarger,CM
噻唑烷二酮可增加组织对胰岛素的敏感性，并对糖尿病肾病和高血压的恶化具有保护作用。肾脏水平的潜在保护机制可能涉及各种未知的基因表达变化。我们检测了肥胖和瘦Zucker大鼠对罗格列酮(文迪雅®)的肾脏基因表达的影响，罗格列酮是一种过氧化体增殖物激活受体(γ亚型)激动剂。对照组和添加罗格列酮(3 mg/kg·bw)的Zucker大鼠饲养12周(n=3)。用Affymetrix大鼠基因组2302.0基因芯片检测大鼠肾脏总mRNA的表达。903个探针组发生显著变化(P<；0.05)，组间变化至少1.5倍。在未经治疗的肥胖大鼠中，相对于LEAN，300套探针增加，244套减少。增加的基因包括上皮性钠通道的β亚单位、对噻嗪敏感的钠-氯共转运体和水通道蛋白3。减少的基因包括血管紧张素转换酶1型。FatiGO分析表明，瘦和肥胖之间改变的基因数量最多的类别是：离子结合、水解酶活性和蛋白质结合。RGZ增加了瘦身和肥胖大鼠解偶联蛋白1(UCP1)、CD36和脂肪酸结合蛋白4(FABP4)的表达。在肥胖大鼠中，RGZ(不再与LEAN不同)对33个基因进行了正常化，包括ACE1、脂肪酸合成酶(FASN)和硬脂酰辅酶A脱饱和酶(SCD1)。对RGZ上调肥胖大鼠基因的系统分析显示，肥胖大鼠的两个主要结点：PPAR-γ和肿瘤坏死因子α(肿瘤坏死因子-α)受到影响。
Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia®), a peroxisome proliferator activated receptor (γ-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kg· bw) for 12 weeks (n= 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P< 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the β-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase (SCD1). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-γ and tumor necrosis factor α (TNF-α).