Involvement of glomerular SREBP-1c in diabetic nephropathy
Involvement of glomerular SREBP-1c in diabetic nephropathy
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DOI：
10.1016/j.bbrc.2007.10.038
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发表时间：
2007-12-21
影响因子：
3.1
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Ishigaki, Naomi;Yamamoto, Takashi;Shimano, Hitoshi
研究了肾小球 SREBP-1c 在糖尿病肾病中的作用。尽管不存在高血糖或高脂血症，但过表达核 SREBP-1c 的 PEPCK 启动子转基因小鼠表现出蛋白尿增加、系膜增殖和基质积累，类似于糖尿病肾病。在没有明显脂质积累的情况下，分离的转基因肾小球具有较高的 TGF beta-1、纤连蛋白和 SPARC 表达。 P47(phox)、p67(phox)和PU.1的基因表达也被激活，伴随着尿液和肾脏中8-OHdG的增加，表明肾小球SREBP-1c可以通过诱导NADPH氧化酶直接引起氧化应激。在 STZ 治疗的糖尿病小鼠中观察到内源性 SREBP-1c 激活的类似变化。最后，SREBP-1 缺失小鼠的糖尿病蛋白尿和氧化应激得到改善。活性和显性失活SREBP-1c的腺病毒过度表达引起MESI3系膜细胞中促纤维化和氧化应激基因表达的一致相互变化。这些数据表明肾小球 SREBP-1c 的激活可能导致糖尿病肾病的出现和/或进展。 (C) 2007 Elsevier Inc. 保留所有权利。
The role of glomerular SREBP-1c in diabetic nephropathy was investigated. PEPCK-promoter transgenic mice overexpressing nuclear SREBP-1c exhibited enhancement of proteinuria with mesangial proliferation and matrix accumulation, mimicking diabetic nephropathy, despite the absence of hyperglycemia or hyperlipidemia. Isolated transgenic glomeruli had higher expression of TGF beta-1, fibronectin, and SPARC in the absence of marked lipid accumulation. Gene expression of P47(phox), p67(phox), and PU.1 were also activated, accompanying increased 8-OHdG in urine and kidney, demonstrating that glomerular SREBP-1c could directly cause oxidative stress through induced NADPH oxidase. Similar changes were observed in STZ-treated diabetic mice with activation of endogenous SREBP-1c. Finally, diabetic proteinuria and oxidative stress were ameliorated in SREBP-1-null mice. Adenoviral overexpression of active and dominant-negative SREBP-I c caused consistent reciprocal changes in expression of both profibrotic and oxidative stress genes in MESI3 mesangial cells. These data suggest that activation of glomerular SREBP-1c could contribute to emergence and/or progression of diabetic nephropathy. (C) 2007 Elsevier Inc. All rights reserved.