ACTIVATION/DEACTIVATION OF RENAL NA+,K+-ATPASE - A FINAL COMMON PATHWAY FOR REGULATION OF NATRIURESIS
ACTIVATION/DEACTIVATION OF RENAL NA+,K+-ATPASE - A FINAL COMMON PATHWAY FOR REGULATION OF NATRIURESIS
复制标题
DOI：
10.1096/fasebj.8.6.8168694
复制
发表时间：
1994-04-01
期刊：
影响因子：
4.8
通讯作者：
GREENGARD, P
中科院分区：
文献类型：
--
作者：
APERIA, A;HOLTBACK, U;GREENGARD, P
肾钠代谢是血压的主要决定因素，它受多种内分泌、自分泌和神经元因素的精确调节。虽然已知这些因子通过影响管状钠重吸收速率来调节钠代谢，但其作用的分子机制尚不清楚。Na+，K+- atp酶在所有管状节段的钠重吸收中起关键作用。该酶的活性可通过磷酸化和去磷酸化动态调节。在这里，我们总结了一些新的和旧的证据，这些证据表明，几种主要的物质被认为参与钠代谢和血压的调节，即抗利尿剂血管紧张素和去甲肾上腺素，以及利尿剂多巴胺和心房钠素肽（ANP），可能通过一个共同的途径实现其作用，该途径涉及肾小管Na+，K+- atp酶的可逆激活/失活。研究了Na+，K+- atp酶活性的调节，使用制备的单近端小管（PT）段，从大鼠肾脏解剖。在生理的、不饱和的Nai浓度下，血管紧张素II和α -肾上腺素能激动剂oxymetazoline刺激Na+、K+- atp酶活性。这些刺激作用被多巴胺和ANP以及它们各自的第二信使cAMP和cGMP阻断。它们也被特异性蛋白磷酸酶2B抑制剂FK506阻断。这些结果表明，去甲肾上腺素、血管紧张素II、多巴胺和ANP对钠排泄的调节可以通过调节肾小管Na+、K+- atp酶活性的双向调节的细胞内蛋白磷酸化级联来解释。
Renal sodium metabolism, a major determinant of blood pressure, is regulated with great precision by a variety of endocrine, autocrine, and neuronal factors. Although these factors are known to regulate sodium metabolism by affecting the rate of tubular sodium reabsorption, the molecular mechanisms by which they act are poorly understood. Na+,K+-ATPase plays a pivotal role for sodium reabsorption in all tubular segments. The activity of this enzyme can be dynamically regulated by phosphorylation and dephosphorylation. Here we summarize both old and new evidence that several major substances believed to be involved in the regulation of sodium metabolism and blood pressure, i.e., the antidiuretic agents angiotensin II and norepinephrine, and the diuretic agents dopamine and atrial natriuretic peptide (ANP), may achieve their effects through a common pathway that involves reversible activation/deactivation of renal tubular Na+,K+-ATPase. Regulation of Na+,K+-ATPase activity was studied using a preparation of single proximal tubule (PT) segments, dissected from rat kidneys. Na+,K+-ATPase activity was stimulated by angiotensin II and the alpha-adrenergic agonist, oxymetazoline, at physiological, nonsaturating Nai concentrations. These stimulatory effects were blocked by dopamine and ANP as well as by their respective second messengers, cAMP and cGMP. They were also blocked by the specific protein phosphatase 2B inhibitor FK506. These results indicate that regulation of sodium excretion by norepinephrine, angiotensin II, dopamine, and ANP can be accounted for by a bidirectionally regulated intracellular protein phosphorylation cascade that modulates the activity of renal tubular Na+,K+-ATPase.