Hypertension of Kcnmb1-/- is linked to deficient K secretion and aldosteronism
Hypertension of Kcnmb1-/- is linked to deficient K secretion and aldosteronism
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DOI：
10.1073/pnas.0904635106
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发表时间：
2009-07-14
影响因子：
11.1
通讯作者：
Sansom, Steven. C.
中科院分区：
文献类型：
--
作者：
Grimm, P. Richard;Irsik, Debra L.;Sansom, Steven. C.
缺乏大钙激活钾通道（BK）β 1亚基（基因，Kcnmb 1;蛋白质，BK-β 1）的小鼠是高血压。这种表型被认为是由血管平滑肌中BK电流减少引起的，其中BK-β 1是辅助亚基。然而，β 1亚基也在肾连接小管（CNT）中表达，CNT是醛固酮敏感性远端肾单位的一部分，在那里它与BK相关并促进K分泌。由于某些形式的高血压与肾功能缺损之间的相关性，特别是在远端肾单位中，确定Kcnmb 1（-/-）高血压是否具有肾起源。我们发现Kcnmb 1（-/-）是高血压，体积扩大，并减少尿钾和钠清除。当动物喂食高钾饮食（5%K; HK）时，这些情况会加剧。用依普利酮（盐皮质激素受体拮抗剂）补充HK喂养的Kcnmb 1（-/-）纠正了液体失衡和70%以上的高血压。最后，血浆[aldo]在基础条件下（对照饮食，0.6%K）在Kcnmb 1（-/-）中升高，并且在饲喂HK饮食时比野生型显著增加。我们的结论是，Kcnmb 1（-/-）的高血压大多数是由于醛固酮增多症，导致肾钾潴留和高钾血症。
Mice lacking the beta 1-subunit (gene, Kcnmb1; protein, BK-beta 1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-beta 1 is an ancillary subunit. However, the beta 1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1(-/-) has a renal origin. We found that Kcnmb1(-/-) are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1(-/-) with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1(-/-) under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1(-/-) is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.