title: Role of the USF1 transcription factor in diabetic kidney disease.
abstract: The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-β1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/-), and homozygous (USF1 -/-) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 -/- diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-β1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 -/- diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-β1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California, Veterans Administration San Diego HealthCare System, La Jolla, 92093, USA.
authors.forename: Amber P
authors.initials: AP
authors.lastname: Sanchez
authors.forename: JingHong
authors.initials: J
authors.lastname: Zhao
authors.forename: Young
authors.initials: Y
authors.lastname: You
authors.forename: Anne-Emilie
authors.initials: AE
authors.lastname: Declèves
authors.forename: Maggie
authors.initials: M
authors.lastname: Diamond-Stanic
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; C497186:Usf2 protein, mouse; C113267:nephrin; D055372:AMP-Activated Protein Kinases