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Involvement of glomerular SREBP-1c in diabetic nephropathy |
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| Authors: | Ishigaki Naomi Yamamoto Takashi Shimizu Yoshio Kobayashi Kazuto Yatoh Shigeru Sone Hirohito Takahashi Akimitsu Suzuki Hiroaki Yamagata Kunihiro Yamada Nobuhiro Shimano Hitoshi |
| Institution: | a Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan b Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan c Department of Nephrology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan |
| Abstract: | 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 TGFβ-1, fibronectin, and SPARC in the absence of marked lipid accumulation. Gene expression of P47phox, p67phox, 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-1c caused consistent reciprocal changes in expression of both profibrotic and oxidative stress genes in MES13 mesangial cells. These data suggest that activation of glomerular SREBP-1c could contribute to emergence and/or progression of diabetic nephropathy. |
| Keywords: | Fatty acids Triglycerides Diabetes Proteinuria Kidney TGF Oxidative stress NADPH oxidase |
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