Lang Florian, Capasso Giovambattista, Schwab Matthias, Waldegger Siegfried
Department of Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Clin Exp Nephrol. 2005 Jun;9(2):91-9. doi: 10.1007/s10157-005-0355-x.
Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11beta-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl- channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%-5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.
几种单基因高血压疾病是由基因突变导致肾小管氯化钠转运功能紊乱和/或调节异常引起的，例如利德尔综合征中肾上皮钠通道（ENaC）的突变、戈登综合征中激酶WNK1（无K）的突变、盐皮质激素受体或11β-羟类固醇脱氢酶的突变。此外，糖皮质激素可治性高血压中醛固酮过度生成会导致严重高血压。相反，钠-钾-2氯协同转运蛋白（NKCC2）、肾外髓质钾通道（ROMK1）和肾上皮氯通道ClCKb/Barttin功能受损会导致巴特综合征，而缺陷性钠-氯协同转运蛋白（NCCT）会导致吉特曼综合征，这两种都是伴有低血压的失盐性疾病。这些单基因疾病很罕见，但说明了肾小管转运在血压调节中的重要性。然而，毫无疑问，肾脏盐重吸收紊乱在原发性高血压中起重要作用。参与肾脏钠转运调节的几个基因的多态性已被证明与血压及高血压患病率相关。将更详细地讨论两个常见基因。第一个基因编码肾氯通道ClCKb。在未筛选的高加索人群中约20%以及未筛选的非洲人群中约40%发现了ClCKb的功能获得性突变，该突变使通道活性增加7至20倍。第二个将更详细讨论的常见基因变异（在未筛选的高加索人群中的患病率为3% - 5%）影响血清和糖皮质激素诱导激酶SGK1，该激酶受盐皮质激素上调并增强ENaC、ROMK和钠-钾ATP酶的活性。这两种基因变异都与血压略有升高有关。SGK1还进一步刺激葡萄糖转运蛋白SGLT1，此外，SGK1基因变异还与体重指数增加相关。
