Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury

Abstract

Liu S, Shi L, Wang S. Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury. Am J Physiol Renal Physiol 293: F1727-F1735, 2007. First published September 19, 2007; doi:10.1152/ajprenal.00316.2007.-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-␤ (TGF-␤), 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-␤ 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 (ϳ6 mo old) exhibited increased urinary albumin excretion. These mice also exhibited glomerular hypertrophy, accompanied by increased TSP1, active TGF-␤, 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. TGF-␤DIABETIC NEPHROPATHY is the most common cause of end-stage renal failure in the United States. About 20 -30% of type 1 and type 2 diabetic patients develop diabetic nephropathy (5). Diabetic nephropathy is characterized by both glomeruosclerosis with thickening of the glomerular basement membrane and mesangial matrix expansion, and tubulointerstitial fibrosis (11). Hyperglycemia is an important factor in the pathogenesis of diabetic nephropathy (32). Hyperglycemia upregulates the expression of a fibrogenic growth factor, transforming growth factor-␤ (TGF-␤), contributing to the development of diabetic nephropathy (29). The importance of TGF-␤ in the development of diabetic nephropathy is well-established. TGF-␤ is involved in both the early and later stages of diabetic nephropathy (3,20,27). Moreover, studies have shown that anti-TGF-␤ antibodies prevent the development of diabetic nephropathy (2, 28), providing a direct evidence for the involvement of TGF-␤ in the pathogenesis of diabetic nephropathy. The fibrogenic effects of TGF-␤ are due to its upregulation of extracellular matrix components, including collagen, fibronectin, osteopontin, and ...

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

“…34,35 Moreover, streptozotocin-treated TSP1 null mice do not develop glomerulosclerosis or podocyte loss, 36 and mice with induced expression of USF2 have increased TSP1 expression, TGF-␤ activity, and renal fibrosis. 37 TSP1 expression correlates with proteinuria in patients with type 2 diabetes, 34 and glycated albumin stimulates increased TSP1 expression and tubular hypertrophy. 38 Moreover, antagonism of TSP1-dependent TGF-␤ activation by treatment with a peptide antagonist of TSP1-dependent TGF-␤ activation, LSKL, reversed myocardial fibrosis and improved left ventricular function by reducing TGF-␤ activity in diabetic rats.…”

Glycated albumin upregulates upstream stimulatory factor 2 gene transcription in mesangial cells

“…We previously demonstrated that USF2 was upregulated in the kidney from diabetic animals as well as in the mesangial cells after acute high-glucose exposure and plays an important role in the development of diabetic nephropathy through regulation of TSP1 and TSP1-dependent TGF-␤ activity (23,30,35). Our current studies revealed a new regulatory mechanism of USF2 expression in mesangial cells under diabetic conditions, e.g., glycated albumin-mediated upregulation of USF2.…”

“…We demonstrated that USF2 binds to an 18-bp sequence in the thrombospondin1 (TSP1) gene promoter and regulates high glucose-induced TSP1 expression and TSP1-dependent TGF-␤ activity in mesangial cells (35). Moreover, overexpression of USF2 stimulates TSP1 expression, TGF-␤ activity, and extracellular matrix protein expression in the kidney and accelerates the development of diabetic nephropathy (23). All these studies suggest that USF2 is an important regulator of diabetic nephropathy.…”

Identificação e caracterização das interações do gene ID1 em células mesangiais humanas.

“…A expressão de USF2 já havia sido demonstrada em células mesangiais [111][112][113][114][115] , e aparenta estar diretamente relacionada com o desenvolvimento de doenças renais crônicas, incluindo a nefropatia diabética. Sua expressão encontra-se aumentada sob condições de altas concentrações de glicose; além disso, trabalhos indicam que a atividade de TGFβ é estimulada pelo fator USF2 [112][113][114][115] .…”

“…Sua expressão encontra-se aumentada sob condições de altas concentrações de glicose; além disso, trabalhos indicam que a atividade de TGFβ é estimulada pelo fator USF2 [112][113][114][115] .…”