Role of the USF1 transcription factor in diabetic kidney disease.
Authors Sanchez AP, Zhao J, You Y, Declèves AE, Diamond-Stanic M, Sharma K
Submitted By Kumar Sharma on 6/7/2011
Status Published
Journal American journal of physiology. Renal physiology
Year 2011
Date Published 8/1/2011
Volume : Pages 301 : F271 - F279
PubMed Reference 21543418
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)-ß1 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-ß1 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-ß1 and renin stimulation in
diabetic kidney disease. AMPK activity may play a key role in high
glucose-induced regulation of USF1.

Investigators with authorship
Kumar SharmaUniversity of California San Diego