High glucose upregulates upstream stimulatory factor 2 in human renal proximal tubular cells through angiotensin II-dependent activation of CREB.
OBJECTIVE
We have previously demonstrated that a transcription factor, upstream stimulatory factor 2 (USF2), regulates glucose-induced thrombospondin 1 expression and transforming growth factor-β activity in mesangial cells, and plays an important role in diabetic glomerulopathy. In this study, we determined whether USF2 expression in renal proximal tubular cells is regulated by glucose and contributes to diabetic tubulointerstitial fibrosis.


METHODS
Human renal proximal tubular cells (HK-2 cells) were treated with normal- or high-glucose medium for 24 h. After treatment, real-time PCR or immunoblotting was used to determine the expression of USF2 and other components of the renin-angiotensin system in HK-2 cells.


RESULTS
High glucose upregulated USF2 expression and increased extracellular matrix accumulation in HK-2 cells; both were inhibited by siRNA-mediated USF2 knockdown. In addition, high glucose stimulated angiotensinogen and renin expression, increased renin activity, and resulted in increased angiotensin II formation. Treatment of HK-2 cells with an angiotensin II receptor 1 (AT1) blocker--losartan--prevented high-glucose-induced USF2 expression and high-glucose-enhanced phosphorylation of CREB (cAMP response element-binding protein).


CONCLUSIONS
Our data established that high glucose stimulated USF2 expression in HK-2 cells, at least in part, through angiotensin II-AT1-dependent activation of CREB, which can contribute to diabetic tubulointerstitial fibrosis.
Visavadiya
Nishant P
NP
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0200, USA.
Li
Yanzhang
Y
Wang
Shuxia
S
D000804:Angiotensin II / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000503:physiopathology; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis; D012084:Renin-Angiotensin System; D015854:Up-Regulation; D051720:Upstream Stimulatory Factors / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D005947:Glucose; D019808:Losartan
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