Wang Conghui, Kawakami-Mori Fumiko, Kang Lei, Ayuzawa Nobuhiro, Ogura Sayoko, Koid Suang Suang, Reheman Latapati, Yeerbolati Alimila, Liu Beibei, Yatomi Yutaka, Chen Xiangmei, Fujita Toshiro, Shimosawa Tatsuo
Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China; Department of Clinical Laboratory, School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Clinical Epigenetics, Research Center for Advancing Science and Technology, The University of Tokyo, Tokyo, Japan.
Kidney Int. 2020 Nov;98(5):1242-1252. doi: 10.1016/j.kint.2020.05.050. Epub 2020 Jun 24.
To investigate the cause of salt sensitivity in a normotensive animal model, we treated rats with a low-dose of the nitric oxide synthase inhibitor, L-NAME, that does not elevate blood pressure per se or induce kidney fibrosis. A high salt diet increased the circulating blood volume both in L-NAME-treated and nontreated animals for the first 24 hours. Thereafter, the blood volume increase persisted only in the L-NAME-treated rats. Blood pressure was higher in the L-NAME-treated group from the start of high salt diet exposure. Within the first 24 hours of salt loading, the L-NAME treated animals failed to show vasodilation and maintained high systemic vascular resistance in response to blood volume expansion. After four weeks on the high salt diet, the slope of the pressure-natriuresis curve was blunted in the L-NAME-treated group. An increase in natriuresis was observed after treatment with hydrochlorothiazide, but not amiloride, a change observed in parallel with increased phosphorylated sodium-chloride cotransporter (NCC). In contrast, a change in blood pressure was not observed in L-NAME-treated NCC-deficient mice fed a high salt diet. Moreover, direct L-NAME-induced NCC activation was demonstrated in cells of the mouse distal convoluted tubule. The vasodilatator, sodium nitroprusside, downregulated phosphorylated NCC expression. The effect of L-NAME on phosphorylated NCC was blocked by both the SPAK inhibitor STOCK2S-26016 and the superoxide dismutase mimetic TEMPO which also attenuated salt-induced hypertension. These results suggest that the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature and that maintaining blood pressure could result in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. Thus, even slightly impaired nitric oxide production may be important in salt sensitivity regulation in healthy rodents.
为了研究正常血压动物模型中盐敏感性的原因，我们用低剂量的一氧化氮合酶抑制剂L-NAME处理大鼠，该抑制剂本身不会升高血压或诱导肾纤维化。高盐饮食在最初24小时内增加了L-NAME处理组和未处理组动物的循环血容量。此后，血容量增加仅在L-NAME处理的大鼠中持续存在。从高盐饮食开始，L-NAME处理组的血压就更高。在盐负荷的最初24小时内，L-NAME处理的动物未表现出血管舒张，并在血容量扩张时维持较高的全身血管阻力。高盐饮食四周后，L-NAME处理组的压力-利钠曲线斜率变钝。用氢氯噻嗪治疗后观察到利钠增加，但用阿米洛利治疗后未观察到，这一变化与磷酸化氯化钠共转运体（NCC）增加平行。相反，在喂食高盐饮食的L-NAME处理的NCC缺陷小鼠中未观察到血压变化。此外，在小鼠远曲小管细胞中证实了L-NAME直接诱导的NCC激活。血管舒张剂硝普钠下调了磷酸化NCC的表达。SPAK抑制剂STOCK2S-26016和超氧化物歧化酶模拟物TEMPO均阻断了L-NAME对磷酸化NCC的作用，二者也减轻了盐诱导的高血压。这些结果表明，正常血压啮齿动物中盐敏感性的起始可能是由于血管系统反应性降低，并且在低剂量L-NAME模型中，由于NCC活性异常，维持血压可能导致循环血容量升高。因此，即使一氧化氮生成稍有受损，在健康啮齿动物的盐敏感性调节中也可能很重要。
