30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

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   Figure 1

   Cells comprising the renal distal nephron. Distal convoluted tubule (DCT) cells express thiazide-sensitive Na–Cl cotransporter (NCC) at the apical membrane. Principal cells of the collecting duct express epithelial Na⁺ Channel (ENaC) and renal outer medullary K⁺ channel (ROMK) at the apical membrane. Intercalated cells are divided into three types; α-intercalated cells express H⁺-ATPase, whereas β-intercalated cells express Cl⁻/HCO₃⁻ exchanger pendrin at the apical membrane. Non-α, non-β intercalated cells are characterized by the expression of both pendrin and H⁺-ATPase at the apical membrane.
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   Figure 2

   Regulation of MR in β-intercalated cells. In principal cells, aldosterone binds to MR and activates ENaC, which drives K⁺ secretion through apical K⁺ channel ROMK. The resultant decrease in plasma K⁺ levels causes MR^S843-P dephosphorylation in β-intercalated cells, allowing aldosterone binding to MR in these cells and increasing pendrin at the plasma membrane. Reproduced, with permission, from Xu N, Hirohama D, Ishizawa K, Chang WX, Shimosawa T, Fujita T, Uchida S & Shibata S (2017) Hypokalemia and pendrin induction by aldosterone. Hypertension [in press].
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   Figure 3

   MR-dependent regulation of NCC in DCT cells. Aldosterone and MR increase serine/threonine kinase SGK1 abundance by regulating its transcription. SGK1 phosphorylates ubiquitin ligase Nedd4-2, which reduces its interaction with exons 11 and 12 of WNK1, preventing WNK1 degradation via the ubiquitin proteasome system (UPS). SGK1 then phosphorylates and increases WNK1 kinase activity. Active WNK1 in turn promotes SPAK and OSR1 activation, which directly stimulates NCC by phosphorylation.
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   Figure 4

   Hypokalemia-dependent regulation of NCC in DCT cells. The decrease in plasma K⁺ levels by aldosterone stimulates the WNK-SPAK/OSR1-NCC cascade via two distinct mechanisms. Firstly, hypokalemia reduces the activity of ubiquitin ligase complex composed of KLHL3/CUL3 by S433 phosphorylation and also by reducing total expression levels, thereby preventing WNK degradation via the ubiquitin proteasome system (UPS) and increasing WNK4 (and likely WNK1) levels. Secondly, hypokalemia reduces intracellular Cl⁻ levels (shown as [Cl]ⁱ) by promoting Cl⁻ efflux; this results in reduced Cl⁻ binding to WNK1/4 and increases the kinase activity.

• © 2017 Society for Endocrinology