Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Jichi Medical University, Shimotsuke, Japan.
Hypertens Res. 2017 Nov;40(11):912-920. doi: 10.1038/hr.2017.31. Epub 2017 Mar 16.
Salt-sensitive hypertension is associated with severe organ damage. Generating oxygen radicals is an integral component of salt-induced kidney damage, and activated leukocytes are important in oxygen radical biosynthesis. We hypothesized that a high-salt diet causes the upregulation of immune-related mechanisms, thereby contributing to the susceptibility of Dahl salt-sensitive rats to hypertensive kidney damage. For verifying the hypothesis, we investigated leukocytes adhering to retinal vessels when Dahl salt-sensitive rats were challenged with a high-salt (8% NaCl) diet using acridine orange fluoroscopy and a scanning laser ophthalmoscope. The high-salt diet increased leukocyte adhesion after 3 days and was associated with a significant increase in mRNA biosynthesis of monocyte chemotactic protein-1 and intercellular adhesion molecule-1 (ICAM-1) -related molecules in the kidney. Losartan treatment did not affect increased leukocyte adhesion during the early, pre-hypertensive phase of high salt loading; however, losartan attenuated the adhesion of leukocytes during the hypertensive stage. Moreover, the inhibition of leukocyte adhesion in the pre-hypertensive stage by anti-CD18 antibodies decreased tethering of leukocytes and was associated with the attenuation of functional and morphological kidney damage without affecting blood pressure elevation. In conclusion, a high-salt challenge rapidly increased leukocyte adhesion through the over-expression of ICAM-1. Increased leukocyte adhesion in the pre-hypertensive stage is responsible for subsequent kidney damage in Dahl salt-sensitive rats. Immune system involvement may be a key component that initiates kidney damage in a genetic model of salt-induced hypertension.
盐敏感性高血压与严重的器官损伤有关。产生氧自由基是盐诱导肾损伤的一个组成部分，而激活的白细胞在氧自由基的生物合成中起着重要作用。我们假设高盐饮食会导致免疫相关机制的上调，从而导致 Dahl 盐敏感大鼠易患高血压性肾损伤。为了验证这一假说，我们使用吖啶橙荧光显微镜和扫描激光检眼镜研究了 Dahl 盐敏感大鼠在高盐（8%NaCl）饮食挑战下视网膜血管内白细胞的黏附情况。高盐饮食在 3 天后增加了白细胞黏附，并且与肾脏中单核细胞趋化蛋白-1 和细胞间黏附分子-1（ICAM-1）相关分子的 mRNA 生物合成显著增加相关。氯沙坦治疗在高盐负荷的早期、高血压前期并未影响白细胞黏附的增加；然而，氯沙坦在高血压期减轻了白细胞的黏附。此外，在高血压前期通过抗 CD18 抗体抑制白细胞黏附可减少白细胞的拴系，并与减轻功能和形态学肾损伤相关，而不影响血压升高。总之，高盐刺激通过过度表达 ICAM-1 迅速增加白细胞黏附。高血压前期白细胞黏附的增加是 Dahl 盐敏感大鼠随后肾损伤的原因。免疫系统的参与可能是引发盐诱导高血压遗传模型肾损伤的关键因素。
