Involvement of glomerular SREBP-1c in diabetic nephropathy.
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.
Ishigaki
Naomi
N
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.
Yamamoto
Takashi
T
Shimizu
Yoshio
Y
Kobayashi
Kazuto
K
Yatoh
Shigeru
S
Sone
Hirohito
H
Takahashi
Akimitsu
A
Suzuki
Hiroaki
H
Yamagata
Kunihiro
K
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D013311:Streptozocin
C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013311:Streptozocin