Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice.
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)-beta 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-beta 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 AT(2) 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-beta 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-beta production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.
Shi
Lihua
L
Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg. Rm. 517, 900 S. Limestone St., Lexington, KY 40536-0200, USA.
Nikolic
Dejan
D
Liu
Shu
S
Lu
Hong
H
Wang
Shuxia
S
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D055785:Gene Knockdown Techniques; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
D016212:Transforming Growth Factor beta; D051720:Upstream Stimulatory Factors; C497186:Usf2 protein, mouse; D000804:Angiotensin II; D012083:Renin