Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo
Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo
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DOI：
10.1681/asn.2005111197
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发表时间：
2006-09-01
影响因子：
13.6
通讯作者：
Brown, Roger W.
中科院分区：
文献类型：
--
作者：
O'Reilly, Michelle;Marshall, Elaine;Brown, Roger W.
WNK1 和 WNK4 是不寻常的丝氨酸/苏氨酸激酶，催化活性位点赖氨酸的位置不典型（WNK：With-No-K[赖氨酸]）。这些 WNK 激酶基因的突变可引起家族性高钾性高血压 (FHHt)，这是一种常染色体显性遗传性高血压、高钾性疾病，表明这种新的 WNK 通路参与血压和电解质平衡的正常调节。先前已鉴定出全长 (WNK1-L) 和短 (WNK1-S) 激酶缺陷型 WNK1 亚型。重要的是，WNK1-S 在肾脏中占绝对优势。最近的非洲爪蟾卵母细胞研究表明，WNK4 通过肾外髓质 K+ 通道抑制噻嗪类敏感共转运蛋白介导的 Na+ 重吸收和 K+ 分泌，现在表明 WNK4 受 WNK1-L 抑制，而 WNK4 本身又受 WNK1-S 抑制。本研究检测了小鼠肾脏中 WNK 通路基因的表达及其体内调控。 WNK1-S和WNK4在远端肾小管中表达最强，在集合管中急剧下降，并且WNK4在粗升肢和致密斑中也有表达。这些表达 WNK1-S 和 WNK4 mRNA 的肾单位片段对长期 NaCl 重吸收、BP、K+ 和酸碱平衡有重大影响，这些过程在 FHHt 中都被破坏。在体内，这种新的 WNK 通路会随着 K+ 摄入量的增加而显着上调 WNK1-S 和 WNK4，而随着 K+ 或 Na+ 摄入量的长期降低，WNK1-S 会减少。两室远端肾单位模型很好地解释了这些体内发现和 FHHt 的病理生理学，WNK 和经典醛固酮途径响应 K+ 平衡、细胞外容量和醛固酮的驱动因素，以及通过远端 Na+ 输送调节电解质平衡和血压的串扰。
WNK1 and WNK4 are unusual serine/threonine kinases with atypical positioning of the catalytic active-site lysine (WNK: With-No-K[lysine]). Mutations in these WNK kinase genes can cause familial hyperkalemic hypertension (FHHt), an autosomal dominant, hypertensive, hyperkalemic disorder, implicating this novel WNK pathway in normal regulation of BP and electrolyte balance. Full-length (WNK1-L) and short (WNK1-S) kinase-deficient WNK1 isoforms previously have been identified. Importantly, WNK1-S is overwhelmingly predominant in kidney. Recent Xenopus oocyte studies implicate WNK4 in inhibition of both thiazide-sensitive co-transporter-mediated Na+ reabsorption and K+ secretion via renal outer medullary K+ channel and now suggest that WNK4 is inhibited by WNK1-L, itself inhibited by WNK1-S. This study examined WNK pathway gene expression in mouse kidney and its regulation in vivo. Expression of WNK1-S and WNK4 is strongest in distal tubule, dropping sharply in collecting duct and with WNK4 also expressed in thick ascending limb and the macula densa. These nephron segments that express WNK1-S and WNK4 mRNA have major influence on long-term NaCl reabsorption, BP, K+, and acid-base balance, processes that all are disrupted in FHHt. In vivo, this novel WNK pathway responds with significant upregulation of WNK1-S and WNK4 with high K+ intake and reduction in WNK1-S on chronic lowering of K+ or Na+ intake. A two-compartment distal nephron model explains these in vivo findings and the pathophysiology of FHHt well, with WNK and classic aldosterone pathways responding to drivers from K+ balance, extracellular volume, and aldosterone and cross-talk through distal Na+ delivery regulating electrolyte balance and BP.