WNK4 kinase inhibits NCC activity. Multiple secondary messengers modulate WNK4 action. L-WNK1 inhibits WNK4, but is suppressed by ks-WNK1. L-WNK1 also phosphorylates OSR1/SPAK, thereby activating NCC. Symbols are as in Figure 1; secondary messenger proteins and ion transporter sizes vary relative to their proposed activity. (A) Our results suggest that SGK1, induced transcriptionally by aldosterone and activated by PI3K, negatively regulates WNK4’s action on NCC by phosphorylating 2 C-terminal serines of WNK4. SGK1 also positively effects ENaC and ROMK activity in the cortical collecting duct (CCD) through regulatory pathways that include SGK1. (B) Schematic proposal of renal response to hypovolemia, through hyperreninemia and/or stimulation of angiotensin II and aldosterone. Here SGK1 and WNK1 target similar C-terminal WNK4 serines for phosphorylation, relieving the WNK4 inhibitory effect on NCC, increasing NCC-mediated Na⁺/Cl^– cotransport (shown by arrow thickness) while diminishing the regulatory value of SGK1 and other mechanisms in the CCD that lead to K⁺ secretion. (C) Schematic proposal of renal response to aldosterone stimulation by hyperkalemia. In the DCT there is upregulation of ks-WNK1 activity, which — by squelching L-WNK1 — leads to heightened WNK4 activity, low SPAK/OSR1 activity, and reduced NCC-mediated NaCl transport. We surmise that SGK1 has a transient effect on WNK4 with downstream ENaC and ROMK activation by SGK1 and other aldosterone-sensitive mechanisms, restoring potassium balance without affecting extracellular volume.