Shi Lihua, Nikolic Dejan, Liu Shu, Lu Hong, Wang Shuxia
Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg. Rm. 517, 900 S. Limestone St., Lexington, KY 40536-0200, USA.
Am J Physiol Renal Physiol. 2009 Feb;296(2):F257-65. doi: 10.1152/ajprenal.90493.2008. Epub 2008 Nov 12.
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.
此前我们证明，上游刺激因子2（USF2）转基因（Tg）小鼠会发生肾病，包括蛋白尿和肾小球肥大，同时肾小球中转化生长因子（TGF）-β和纤连蛋白的积累增加。然而，USF2过表达诱导肾损伤的机制尚不清楚。已有研究表明，USF可调节肾素表达。此外，肾素-血管紧张素系统（RAS）在肾脏疾病中起重要作用。因此，在本研究中，我们检测了USF2对肾脏以及USF2（Tg）小鼠系膜细胞中RAS调节的影响。我们还确定了USF2介导的RAS调节在系膜细胞TGF-β产生中的作用。我们的数据表明，USF2（Tg）小鼠肾脏中的肾素和血管紧张素（ANG）II水平升高。相比之下，RAS其他组分如肾素受体、血管紧张素原、血管紧张素转换酶（ACE）、ACE2、血管紧张素1a（AT（1a））受体和AT（2）受体在USF2（Tg）小鼠中的肾脏表达未发生改变。同样，从USF2（Tg）小鼠分离的系膜细胞中肾素和ANG II水平升高。过表达USF2的系膜细胞中TGF-β的产生也增加，这可被小干扰RNA介导的肾素基因敲低或RAS阻断（依那普利或氯沙坦）所阻断。总的来说，这些结果表明，USF2促进肾脏肾素表达并刺激ANG II生成，导致肾内RAS激活。此外，肾素依赖性ANG II生成介导了USF2对系膜细胞TGF-β产生的影响，这可能有助于USF2（Tg）小鼠肾病的发展。
