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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/F257    most recent 90493.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shi, L. Articles by Wang, S. Search for Related Content PubMed PubMed Citation Articles by Shi, L. Articles by Wang, S.

Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice

¹Graduate Center for Nutritional Sciences and ²Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky

Submitted 15 August 2008 ; accepted in final form 9 November 2008

Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-β and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-β production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT_1a) receptor, and AT₂ receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-β production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-β production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.

transforming growth factor-β