Division of Nephrology, Department of Internal Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Hypertension. 2013 Oct;62(4):712-8. doi: 10.1161/HYPERTENSIONAHA.113.01203. Epub 2013 Aug 12.
Inappropriate activation of the intrarenal renin-angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid-binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid-binding protein on post-angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid-binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II-induced SSHT. Overexpression of tubular liver-type fatty acid-binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin-angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid-binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid-binding protein, and found that gene transfection of liver-type fatty acid-binding protein and, in part, recombinant liver-type fatty acid-binding protein administration had significantly attenuated angiotensin II-induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid-binding protein in the proximal tubules may protect against angiotensin II-induced SSHT by attenuating activation of the intrarenal renin-angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid-binding protein in the proximal tubules may be a novel therapeutic target for SSHT.
肾内肾素-血管紧张素系统的不适当激活会导致活性氧的产生和肾小管间质炎症，这有助于盐敏感性高血压（SSHT）的发生。肝型脂肪酸结合蛋白在人类的近端肾小管中表达，但在啮齿动物中不表达，可能发挥内源性抗氧化作用。本研究的目的是研究肝型脂肪酸结合蛋白在血管紧张素 II 后 SSHT 模型中的抗氧化作用，该模型在近端肾小管中选择性过表达人肝型脂肪酸结合蛋白的转基因小鼠。转基因小鼠对血管紧张素 II 诱导的 SSHT 有明显的保护作用。管状肝型脂肪酸结合蛋白的过表达可防止肾内 T 细胞浸润，并减少活性氧的产生、肾内肾素-血管紧张素系统的激活和单核细胞趋化蛋白-1 的表达。我们还使用具有或不具有重组肝型脂肪酸结合蛋白的鼠近端肾小管细胞系以及转染人肝型脂肪酸结合蛋白的鼠近端肾小管细胞系进行了体外研究，发现肝型脂肪酸结合蛋白的基因转染和部分重组肝型脂肪酸结合蛋白的给药可显著减轻血管紧张素 II 诱导的活性氧的产生以及血管紧张素原和单核细胞趋化蛋白-1 在鼠近端肾小管细胞系中的表达。这些发现表明，近端肾小管中的肝型脂肪酸结合蛋白可能通过减轻肾内肾素-血管紧张素系统的激活以及减少氧化应激和肾小管间质炎症来保护血管紧张素 II 诱导的 SSHT。目前的数据表明，近端肾小管中的肝型脂肪酸结合蛋白可能是 SSHT 的一个新的治疗靶点。
