School of Pharmacy and Biochemistry, Department of Pathophysiology, Pharmacology and Clinical Biochemistry, University of Buenos Aires, INFIBIOC, CONICET, Buenos Aires, Argentina.
J Cell Physiol. 2010 Jul;224(1):41-8. doi: 10.1002/jcp.22087.
The aim of this work was to study the role of local intrarenal angiotensin II (Ang II) and the oxidative stress in the up-regulation of pro-inflammatory cytokines expression observed in rats submitted to an acute sodium overload. Sprague-Dawley rats were infused for 2 h with isotonic saline solution (Control group) and with hypertonic saline solution alone (Na group), plus the AT1 receptor antagonist losartan (10 mg kg(-1) in bolus) (Na-Los group), or plus the superoxide dismutase mimetic tempol (0.5 mg min(-1) kg(-1)) (Na-Temp group). Mean arterial pressure, glomerular filtration rate, and fractional sodium excretion (FE(Na)) were measured. Ang II, NF-kappaB, hypoxia inducible factor-1 alpha (HIF-1 alpha), transforming growth factor beta1 (TGF-beta1), smooth muscle actin (alpha-SMA), endothelial nitric oxide synthase (eNOS), and RANTES renal expression was evaluated by immunohistochemistry. Ang II, NF-kappaB, and TGF-beta1 and RANTES early inflammatory markers were overexpressed in Na group, accompanied by enhanced HIF-1 alpha immunostaining, lower eNOS expression, and unmodified alpha-SMA. Losartan and tempol increased FE(Na) in sodium overload group. Although losartan reduced Ang II and NF-kappaB staining and increased eNOS expression, it did not restore HIF-1 alpha expression and did not prevent inflammation. Conversely, tempol increased eNOS and natriuresis, restored HIF-1 alpha expression, and prevented inflammation. Early inflammatory markers observed in rats with acute sodium overload is associated with the imbalance between HIF-1 alpha and eNOS expression. While both losartan and tempol increased natriuresis and eNOS expression, only tempol was effective in restoring HIF-1 alpha expression and down-regulating TGF-beta1 and RANTES expression. The protective role of tempol, but not of losartan, in the inflammatory response may be associated with its greater antioxidant effects.
本研究旨在探讨局部肾内血管紧张素 II（Ang II）和氧化应激在急性钠超负荷大鼠促炎细胞因子表达上调中的作用。Sprague-Dawley 大鼠连续 2 小时输注等渗生理盐水（对照组）、高渗盐水（Na 组）、外加血管紧张素受体拮抗剂氯沙坦（10 mg·kg-1·bolus）（Na-Los 组）或外加超氧化物歧化酶模拟物替米沙坦（0.5 mg·min-1·kg-1）（Na-Temp 组）。检测平均动脉压、肾小球滤过率和钠排泄分数（FE(Na)）。采用免疫组织化学方法检测 Ang II、核因子-κB（NF-κB）、缺氧诱导因子-1α（HIF-1α）、转化生长因子-β1（TGF-β1）、平滑肌肌动蛋白（α-SMA）、内皮型一氧化氮合酶（eNOS）和 RANTES 肾脏表达。结果显示，Na 组大鼠 Ang II、NF-κB 和 TGF-β1 及 RANTES 等早期炎症标志物过度表达，同时伴有 HIF-1α免疫染色增强、eNOS 表达降低和α-SMA 无改变。氯沙坦和替米沙坦增加了钠超负荷大鼠的 FE(Na)。虽然氯沙坦降低了 Ang II 和 NF-κB 染色并增加了 eNOS 表达，但未能恢复 HIF-1α表达，也未能阻止炎症反应。相反，替米沙坦增加了 eNOS 和钠排泄，恢复了 HIF-1α表达，并防止了炎症。急性钠超负荷大鼠的早期炎症标志物与 HIF-1α和 eNOS 表达失衡有关。氯沙坦和替米沙坦均能增加钠排泄和 eNOS 表达，但只有替米沙坦能有效恢复 HIF-1α表达并下调 TGF-β1 和 RANTES 表达。替米沙坦而非氯沙坦在炎症反应中的保护作用可能与其更强的抗氧化作用有关。
