Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Microbiology, Heersink School of Medicine, Immunology Institute, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Acta Physiol (Oxf). 2024 Sep;240(9):e14201. doi: 10.1111/apha.14201. Epub 2024 Jul 15.
We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism.
Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured.
We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling.
We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.
我们旨在通过组蛋白去乙酰化酶 1（HDAC1）依赖性机制检验高盐饮食（HS）损害肾脏微血管内皮细胞中一氧化氮（NO）信号的假说。
雄性 Sprague Dawley 大鼠给予正常盐饮食（NS；0.49%NaCl）或 HS（4%NaCl）喂养 2 周。通过测量血液灌流的近髓肾单位（JMN）制备中 L-NAME 诱导的入球小动脉收缩来评估 NO 信号。在该制备中，用来自匹配或不同饮食的供体大鼠的血液对肾脏进行灌流。使用磁性激活细胞分选分离肾脏内皮细胞，并测量 HDAC1 活性。
我们发现 HS 诱导入球小动脉中 NO 信号受损，这可通过 HDAC1 抑制剂 MS-275 恢复。与这些发现一致，肾脏内皮细胞中 HDAC1 活性增加。我们进一步发现，NO 的丧失依赖于供体血液的饮食，而不是肾脏供体的饮食，且 HS 喂养大鼠的血浆足以诱导 NO 信号受损。这表明存在一种我们称之为血浆衍生的内皮功能障碍介质（PDEM）的体液因子。抗氧化剂 PEG-SOD 和 PEG-catalase 以及 NOS 辅因子四氢生物蝶呤的预处理可恢复 NO 信号。
我们得出结论，HS 通过 PDEM 激活内皮细胞中的 HDAC1，导致 NO 信号减少。该研究为高盐饮食降低肾脏微血管内皮细胞中一氧化氮信号的分子机制提供了新的见解。
