Involvement of glomerular SREBP-1c in diabetic nephropathy.

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 TGFbeta-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.

• Authors: Naomi Ishigaki, Takashi Yamamoto, Yoshio Shimizu, Kazuto Kobayashi, Shigeru Yatoh, Hirohito Sone, Akimitsu Takahashi, Hiroaki Suzuki, Kunihiro Yamagata, Nobuhiro Yamada, Hitoshi Shimano
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 364 Issue 3 Pg. 502-8 (Dec 21 2007) ISSN: 1090-2104 [Electronic] United States
• PMID: 17961514 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Streptozocin

Topics

• Animals
• Diabetes Mellitus, Experimental (chemically induced, metabolism)
• Diabetic Nephropathies (metabolism)
• Humans
• Kidney Glomerulus (drug effects, metabolism)
• Mice
• Mice, Transgenic
• Sterol Regulatory Element Binding Protein 1 (metabolism)
• Streptozocin