TY - JOUR
T1 - Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice
AU - Shi, Lihua
AU - Nikolic, Dejan
AU - Liu, Shu
AU - Lu, Hong
AU - Wang, Shuxia
PY - 2009/2
Y1 - 2009/2
N2 - Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albu-minuria 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, angio-tensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT1a) 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.
AB - Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albu-minuria 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, angio-tensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT1a) 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.
KW - Transforming growth factor-β
UR - http://www.scopus.com/inward/record.url?scp=60549085228&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60549085228&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.90493.2008
DO - 10.1152/ajprenal.90493.2008
M3 - Article
C2 - 19004931
AN - SCOPUS:60549085228
SN - 1931-857X
VL - 296
SP - F257-F265
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 2
ER -