Early and sustained inhibition of nuclear factor-κB prevents hypertension in spontaneously hypertensive rats
Early and sustained inhibition of nuclear factor-κB prevents hypertension in spontaneously hypertensive rats
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DOI：
10.1124/jpet.105.088062
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发表时间：
2005-10-01
影响因子：
3.5
通讯作者：
Vaziri, ND
中科院分区：
文献类型：
--
作者：
Rodríguez- Iturbe, B;Ferrebuz, A;Vaziri, ND
已有令人信服的证据表明氧化应激和肾间质炎症的相互作用以及它们在实验动物高血压发病机制中的相互作用。自发性高血压大鼠(SHR)肾间质炎症伴随并主要由氧化还原敏感的促炎性核转录因子-kappaB(NF-kappa B)激活所致。因此，本研究旨在验证一种假设，即在疾病的早期开始长期抑制核因子-kappaB可以减轻自发性高血压大鼠的肾间质炎症和高血压。为此，我们给7-25周龄的SHR注射了公认的核因子-kappa B抑制剂吡咯烷二硫代氨基甲酸酯(PDTC)(每天100 mg/kg)，并将结果与赋形剂治疗的SHR进行了比较。以Wistar京都(WKY)大鼠为对照。未经治疗的自发性高血压大鼠动脉压显著升高，核因子-kappaB活性增强，细胞间黏附分子(ICAM)-1和巨噬细胞化学吸引分子-1(MCP-1)的原位mRNA表达增加，间质内淋巴细胞、巨噬细胞和血管紧张素Ⅱ阳性细胞聚集。PDTC可抑制血压升高，并使肾皮质核因子-kappaB活性及ICAM-1和MCP-1表达正常化。伴随而来的是免疫细胞、血管紧张素II表达细胞和肾组织丙二醛含量显著减少，达到与对照组WKY大鼠相同的水平。结果提示，核因子-kappaB介导的肾内炎性反应在SHR高血压发病机制中起重要作用。
Compelling evidence has emerged pointing to the interaction of oxidative stress and renal interstitial inflammation and their mutual contribution to the pathogenesis of hypertension in experimental animals. Renal interstitial inflammation in spontaneously hypertensive rats (SHR) is accompanied by and largely due to activation of redox-sensitive, proinflammatory nuclear transcription factor-kappa B (NF-kappa B). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-kappa B, beginning early in the course of the disease, may attenuate renal interstitial inflammation and hypertension in SHR. To this end, we administered the reputed NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC) (100 mg/kg daily intraperitoneally) to SHR from 7 to 25 weeks of age and compared the results with vehicle-treated SHR. Vehicle-treated and PDTC-treated Wistar Kyoto (WKY) rats served as controls. The untreated SHR exhibited a significant rise in arterial pressure; increased NF-kappa B activation, elevated intercellular adhesion molecule (ICAM)-1 and in situ mRNA macrophage chemoattractant molecule-1 (MCP-1) expressions; and interstitial accumulation of lymphocytes, macrophages, and angiotensin-II-positive cells. PDTC administration prevented the rise in blood pressure, and normalized renal cortical NF-kappa B activity as well as ICAM-1 and MCP-1 expressions. This was accompanied by a significant reduction in infiltration of immune cells, angiotensin II-expressing cells, and renal tissue malondialdehyde content to values that matched those found in the control WKY rats. Results suggest that NF-kappa B-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.