Understanding Potassium Homeostasis Using Human and Mouse Genetic Models

Date

2013-01-17

Authors

Cheng, Chih-Jen

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Abstract

Potassium homeostasis is one of the most sophisticated processes involving multiple organs in mammals. Many physiological functions, such as excitability of muscles and neurons, rely on stable extracellular potassium concentration. To maintain potassium homeostasis, endogenous factors including hormones and peptides regulate the activity of potassium transporters in many organs, especially skeletal muscles and kidneys, in response to different conditions. To study the perplexed regulations of potassium transporters, I choose two genetic models of human potassium disorders, hypokalemic periodic paralysis (hypoPP) and pseudohypoaldosteronism type II (PHA2). Patients with hypoPP are characterized with ictal hypokalemia and muscle paralysis. HypoPP can be divided into familial and non-familial forms. Recent studies have revealed the pathogenesis of familial hypoPP. However, the pathogenesis of non-familial hypoPP, mainly composed of thyrotoxic or sporadic periodic paralysis (TPP/SPP), is mostly unknown. A novel muscle-specific inward-rectifying potassium (Kir) channel, Kir2.6, has been recently suggested to play a role in TPP. Here, I focus on studying the role of Kir channels in non-familial hypoPP and propose the disease mechanisms to explain hypokalemia and muscle paralysis. PHA2 is a genetic disorder caused by mutations on with-no-lysine kinase 1 or 4 (WNK1/4) and featured with hyperkalemia and hypertension. Studies in PHA2 have revealed that WNK kinases regulate renal sodium transporters and potassium channels. WNK1 enhances the endocytosis of renal outer medullary potassium (ROMK) channel through an intersectin-dependent mechanism, but the upstream regulator is still unknown. Here, I clarified that the phosphoinositol-3-kinase-induced activation of Akt1/SGK can phosphorylate threonin 58 of WNK1 and thus inhibits ROMK current in cultured cells. In addition to full-length WNK1, the kinase-deficient WNK1 isoform, kidney-specific WNK1 (KS-WNK1), also participates in the regulation of renal sodium and potassium handling. Previous studies have shown that high potassium intake enhances KS-WNK1 expression and suppresses renal sodium reabsorption in thick ascending limb (TAL). However, the localization and function of KS-WNK1 in TAL are still debatable. Here, I used KS-WNK1 genetic mouse models to demonstrate that KS-WNK1 is present and function to inhibit sodium reabsorption in cortical TAL. These results contribute to the understanding of potassium homeostasis in skeletal muscle and kidney.

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