尿酸通过TLR2/4激活脂肪组织局部RAS在肥胖性高血压中的作用及机制研究

Multiple evidences have demonstrated that the elevated serum uric acid levels contribute to the occurrence of obesity-related hypertension, despite of the unclear underlying mechanisms. Based on our previous work, we found that uric acid independently contributed to angiotensinogen (AGT) concentrations in patients with obesity hypertension. We also found that the elevated uric acid upregulated local renin-angiotensin system in 3T3-L1 adipocytes, which caused an increase in the expression of AGT and angiotensinⅡ (AngⅡ). However, the underlying signal pathway is not fully understood. It is demonstrated that adipose tissue inflammation is one of important links between hyperuricemia and obesity-related hypertension. The inflammation induced by toll-like receptor 2/4 (TLR2/4) activation plays a key role in blood pressure regulation, the mechanism of which involves upregulation of RAS. Hence, we could speculate that uric acid may be involved in the pathogenesis of obesity-related hypertension via activation of adipose tissue local RAS, which is mediated by TLR2/4 inflammation signal pathway. Therefore, the study is designed as follows: 1) Obese hypertensive rats with hyperuricemia will be treated with uric acid-lowering drugs or TLR2/4 siRNA. The vivo experiments are aimed to investigate whether uric acid could induce inflammation and upregulate local RAS in adipose tissue via TLR2/4 signal pathway, by which uric acid is involved in the pathogenesis of obesity-related hypertension. 2) The cultured adipocytes will be challenged with uric acid with or without the interruption of TLR2/4 and (or) AngⅡ receptor, through which to reveal whether uric acid could increase the expression of local RAS in adipocytes via inflammation signal pathway related with TLR2/4. Through these work, we try to demonstrate the new underlying mechanisms of uric acid implicated in the occurrence of obesity-related hypertension, which could provide new ideas for the prevention and treatment of obesity-related hypertension.

血尿酸升高参与肥胖性高血压的发病，但具体机制尚未阐明。我们的前期研究发现，肥胖性高血压患者血尿酸与血管紧张素原（AGT）水平正相关；高尿酸上调3T3-L1脂肪细胞肾素-血管紧张素系统（RAS），使AGT、血管紧张素Ⅱ（AngⅡ）表达增加，但具体分子机制尚不清楚。脂肪组织炎症是联系尿酸和肥胖性高血压发病的重要纽带。Toll样受体（TLR）2/4活化诱导的炎症反应对机体血压的影响与RAS激活有关。我们假设：尿酸通过TLR2/4炎症信号通路激活脂肪组织局部RAS，参与肥胖性高血压的发病。本项目对肥胖伴高尿酸血症的高血压大鼠降尿酸干预或阻断其TLR2/4表达，以尿酸干预体外培养的脂肪细胞，阻断TLR2/4和（或）AngⅡ受体，观察尿酸是否通过TLR2/4激活脂肪组织炎症，继而上调脂肪组织局部RAS，参与肥胖性高血压发病。旨在探讨尿酸参与肥胖性高血压发病新的可能机制，为肥胖性高血压的防治提供新思路。

高尿酸血症（Hyperuricemia, HUA）在肥胖性高血压患者群中十分常见。大量证据表明，血尿酸升高不仅预测高血压的发病风险，而且参与了高血压的发生、发展。我们的前期工作发现，尿酸上调3T3-L1脂肪细胞肾素-血管紧张素系统（Renin-angiotensin system, RAS）表达，但所涉及的信号通路尚未阐明。深入研究尿酸在肥胖性高血压的作用及分子机制，对进行有效的临床防治具有重要的意义。本研究的主要发现如下：①降尿酸治疗可以抑制脂肪组织炎症，下调脂肪组织RAS，逆转和改善肥胖性高血压的发生、发展；②阻断Toll样受体（Toll-like receptor, TLR）2和TLR4显著降低高尿酸大鼠的血压，减轻大鼠脂肪组织炎症反应，下调脂肪组织RAS表达；③尿酸上调体外培养的脂肪细胞TLR2和TLR4表达，该作用具有浓度和时间依赖性；④阻断脂肪细胞TLR2和TLR4明显减少高尿酸诱导炎症反应，下调局部RAS表达；⑤炎症因子肿瘤坏死因子-α（Tumor necrosis factor-α, TNF-α）或白介素-6（Interleukin-6, IL-6）可上调脂肪细胞局部RAS表达。据此，我们得出结论：尿酸可能通过TLR2/4炎症通路激活脂肪组织局部RAS，参与肥胖性高血压的发病。