Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury.
Diabetic nephropathy is the most common cause of end-stage renal failure in the United States. Hyperglycemia is an important factor in the pathogenesis of diabetic nephropathy. Hyperglycemia upregulates the expression of transforming growth factor-beta (TGF-beta), which stimulates extracellular matrix deposition in the kidney, contributing to the development of diabetic nephropathy. Our previous studies demonstrated that the transcription factor, upstream stimulatory factor 2 (USF2), was upregulated by high glucose, which bound to an 18-bp sequence in the thrombospondin 1 (TSP1) gene promoter and regulated high glucose-induced TSP1 expression and TGF-beta activity in mesangial cells, suggesting that USF2 might play a role in the development of diabetic nephropathy. In the present studies, we examined the effect of overexpression of USF2 on the development of diabetic nephropathy. Type 1 diabetes was induced in USF2 transgenic mice [USF2 (Tg)] and their wild-type littermates (WT) by injection of streptozotocin. Four groups of mice were studied: control WT, control USF2 (Tg), diabetic WT, and diabetic USF2 (Tg). Mice were killed after 15 wk of diabetes onset. At the end of studies, control USF2 (Tg) mice ( approximately 6 mo old) exhibited increased urinary albumin excretion. These mice also exhibited glomerular hypertrophy, accompanied by increased TSP1, active TGF-beta, fibronectin accumulation in the glomeruli compared with control WT littermates. Type 1 diabetes onset further augmented the urinary albumin excretion and glomerular hypertrophy in the USF2 (Tg) mice. These findings suggest that overexpression of USF2 accelerates the development of diabetic nephropathy.
Liu
Shu
S
Graduate Center for Nutritional Sciences, University of Kentucky, Wethington Bldg. Rm 517, 900 S. Limestone St., Lexington, KY 40536, USA.
Shi
Lihua
L
Wang
Shuxia
S
D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005353:Fibronectins / Q000378:metabolism; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
D005353:Fibronectins; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D051720:Upstream Stimulatory Factors; C497186:Usf2 protein, mouse