Rosón María I, Cao Gabriel, Della Penna Silvana, Gorzalczany Susana, Pandolfo Marcela, Toblli Jorge E, Fernández Belisario E
Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Hypertens Res. 2008 Apr;31(4):707-15. doi: 10.1291/hypres.31.707.
Angiotensin II (Ang II) promotes sodium-retention, cell growth and fibrosis in addition to its classical effects on blood pressure and fluid homeostasis. In this study we examined whether low and non-hypertensive doses of exogenous Ang II could enhance the intrarenal expression of transforming growth factor-beta1 (TGF-beta1) observed in rats submitted to sodium overload. Sprague-Dawley-rats were infused for 2 h with 0.1 and 5 microg kg(-1) h(-1) Ang II (Ang 0.1 and Ang 5, respectively) together with saline solution at four different concentrations (isotonic and Na 0.5 mol L(-1), Na 1.0 mol L(-1) and Na 1.5 mol L(-1)). Renal function and mean arterial blood pressure (BP) were measured. The renal distributions of TGF-beta1, alpha-smooth-muscle-actin (alpha-SMA) and nuclear factor-kappaB (NF-kappaB) were evaluated by immunohistochemistry. While the Ang 0.1 groups were normotensive, the Ang 5 groups developed arterial hypertension progressively, and the highest blood pressure values were observed when rats were simultaneously infused with Na 1.5 mol L(-1). Glomerular function was not altered in any group. In cortical tubules, all groups infused with Ang II (0.1 and 5) and hypertonic saline solution (HSS) showed an increase in TGF-beta1 immunostaining compared to those infused with HSS alone. In medullary tubules, only the Ang 5-Na 0.5 group showed a significant increase in TGF-beta 1 immunostaining compared to the Na 0.5 group. Peritubular positive staining for alpha-SMA was present in groups receiving Ang alone or Ang-Na, in a sodium concentration-dependent manner. In cortical-tubules, NF-kappaB immunostaining was significantly increased in the Ang groups in comparison with the control and in Ang-Na 0.5 and Ang-Na 1.0 groups in comparison with the Na 0.5 mol L(-1) and Na 1.5 mol L(-1) groups, respectively, except in the case of the Ang 0.1-Na 1.5 mol L(-1) and Ang 5-Na 1.5 mol L(-1) groups. Moreover, Ang II and sodium overload induced additional changes in TGF-beta1, alpha-SMA and NF-kappaB immunostanding in glomeruli, medullary tubules and renal vessels. In conclusion, the interaction of Ang II with acute-sodium overload exacerbated intrarenal TGF-beta1, alpha-SMA and NF-kappaB expression, independently from changes in blood pressure levels, in normal rats.
血管紧张素II（Ang II）除了对血压和液体平衡具有经典作用外，还能促进钠潴留、细胞生长和纤维化。在本研究中，我们检测了低剂量和非高血压剂量的外源性Ang II是否能增强钠超载大鼠肾内转化生长因子-β1（TGF-β1）的表达。将Sprague-Dawley大鼠分别以0.1和5微克·千克⁻¹·小时⁻¹的剂量（分别为Ang 0.1和Ang 5）输注Ang II 2小时，同时输注四种不同浓度的盐溶液（等渗溶液以及0.5摩尔·升⁻¹、1.0摩尔·升⁻¹和1.5摩尔·升⁻¹的氯化钠溶液）。测量大鼠的肾功能和平均动脉血压（BP）。通过免疫组织化学评估TGF-β1、α-平滑肌肌动蛋白（α-SMA）和核因子-κB（NF-κB）在肾脏中的分布。Ang 0.1组血压正常，而Ang 5组逐渐出现动脉高血压，当大鼠同时输注1.5摩尔·升⁻¹氯化钠溶液时观察到最高血压值。所有组的肾小球功能均未改变。在皮质肾小管中，与单独输注高渗盐溶液（HSS）的组相比，所有输注Ang II（0.1和5）和高渗盐溶液的组TGF-β1免疫染色均增加。在髓质肾小管中，与0.5摩尔·升⁻¹氯化钠溶液组相比，只有Ang 5-0.5摩尔·升⁻¹氯化钠溶液组TGF-β1免疫染色显著增加。单独接受Ang或Ang-氯化钠溶液的组中，肾小管周围α-SMA呈阳性染色，且呈钠浓度依赖性。在皮质肾小管中，与对照组相比，Ang组NF-κB免疫染色显著增加，与0.5摩尔·升⁻¹和1.5摩尔·升⁻¹氯化钠溶液组相比，Ang-0.5摩尔·升⁻¹氯化钠溶液组和Ang-1.0摩尔·升⁻¹氯化钠溶液组NF-κB免疫染色也显著增加，但Ang 0.1-1.5摩尔·升⁻¹氯化钠溶液组和Ang 5-1.5摩尔·升⁻¹氯化钠溶液组除外。此外，Ang II与钠超载相互作用导致肾小球、髓质肾小管和肾血管中TGF-β1、α-SMA和NF-κB免疫染色出现额外变化。总之，在正常大鼠中，Ang II与急性钠超载的相互作用加剧了肾内TGF-β1、α-SMA和NF-κB的表达，且与血压水平变化无关。
