PDF(Pubmed)
Abstract：
The nitric oxide (NO)-generating enzyme, NO synthase-1β (NOS1β), is essential for sodium (Na+ ) homeostasis and blood pressure control. We previously showed that collecting duct principal cell NOS1β is critical for inhibition of the epithelial sodium channel (ENaC) during high Na+ intake. Previous studies on freshly isolated cortical collecting ducts (CCD) demonstrated that exogenous NO promotes basolateral potassium (K+ ) conductance through basolateral channels, presumably Kir 4.1 (Kcnj10) and Kir 5.1 (Kcnj16). We, therefore, investigated the effects of NOS1β knockout on Kir 4.1/Kir 5.1 channel activity. Indeed, in CHO cells overexpressing NOS1β and Kir 4.1/Kir 5.1, the inhibition of NO signaling decreased channel activity. Male littermate control and principal cell NOS1β knockout mice (CDNOS1KO) on a 7-day, 4% NaCl diet (HSD) were used to detect changes in basolateral K+ conductance. We previously demonstrated that CDNOS1KO mice have high circulating aldosterone despite a high-salt diet and appropriately suppressed renin. We observed greater Kir 4.1 cortical abundance and significantly greater Kir 4.1/Kir 5.1 single-channel activity in the principal cells from CDNOS1KO mice. Moreover, blocking aldosterone action with in vivo spironolactone treatment resulted in lower Kir 4.1 abundance and greater plasma K+ in the CDNOS1KO mice compared to controls. Lowering K+ content in the HSD prevented the high aldosterone and greater plasma Na+ of CDNOS1KO mice and normalized Kir 4.1 abundance. We conclude that during chronic HSD, lack of NOS1β leads to increased plasma K+ , enhanced circulating aldosterone, and activation of ENaC and Kir 4.1/Kir 5.1 channels. Thus, principal cell NOS1β is required for the regulation of both Na+ and K+ by the kidney.
摘要：
一氧化氮（NO）生成酶，一氧化氮合酶-1β（NOS1β），对于钠（Na+）稳态和血压控制至关重要。我们先前表明，在高Na摄入期间，收集导管主细胞NOS1β对于抑制上皮钠通道（ENaC）至关重要。先前对新鲜分离的皮质集合管（CCD）的研究表明，外源性NO通过基底外侧通道促进基底外侧钾（K）电导，大概是基尔4.1（Kcnj10）和基尔5.1（Kcnj16）。我们,因此,研究了NOS1β敲除对Kir4.1/Kir5.1通道活性的影响。的确,在过表达NOS1β和Kir4.1/Kir5.1的CHO细胞中，NO信号传导的抑制降低了通道活性。雄性同窝对照和主细胞NOS1β敲除小鼠（CDNOS1KO）在7天，4%NaCl日粮(HSD)检测基底外侧K+电导的变化。我们先前证明，尽管高盐饮食和适当抑制肾素，CDNOS1KO小鼠仍具有高循环醛固酮。我们在CDNOS1KO小鼠的主要细胞中观察到更高的Kir4.1皮质丰度和更高的Kir4.1/Kir5.1单通道活性。此外，与对照组相比，体内螺内酯治疗阻断醛固酮作用导致CDNOS1KO小鼠中Kir4.1丰度降低，血浆K增加。降低HSD中的K含量可防止CDNOS1KO小鼠的高醛固酮和更高的血浆Na，并使Kir4.1丰度正常化。我们得出结论，在慢性HSD期间，缺乏NOS1β导致血浆K+增加，增强循环醛固酮，并激活ENaC和Kir4.1/Kir5.1通道。因此，主要细胞NOS1β是肾脏调节Na和K所必需的。
