Mechanism of Impaired Potassium Transport in Pseudohypoaldosteronism

Pseudohypoaldosteronism type II (PHAII) is a disease featuring increased renal NaCl reabsorption and impaired K + secretion. It is caused by “with no lysine kinase-4 (WNK4)” gene mutation, also known as Gordon syndrome, an autosomal-dominant disorder associated with hyperkalemia. WNK4 is a key regulator of distal nephron Na + and K + transport and electrolyte homeostasis. Wild-type WNK inhibits early distal NaCl cotransport, reducing NaCl reabsorption, and inhibits K + secretion. Mutation of WNK4 increases NaCl absorption by elevated Thiazide-sensitive NaCl-cotransport (TSC, or NCC) activity, causing hypertension. WNK4 mutation caused hyperkalemia by reduced distal nephron K + section, presumably by reduced ROMK activity. The distal nephron K + secretion is mediated by both the “renal outer medullary potassium (ROMK) channel” and the “large conductance Ca 2+ -activated K + (BK, or Maxi-K)” channel. However, the direct measurement of K + secretion in distal nephrons and the relative roles of the ROMK and the Maxi-K channel-mediated K + secretion in the WNK4-PHAII mutant (TgWnk4 PHAII ) mice had never been studied. We studied the mechanism of impaired K + transport in TgWnk4 PHAII mutant mice. Stationary microperfusion with double-barreled microelectrodes was performed “in vivo”, and potassium concentration was measured in cortical distal tubules. The potassium secretion (J K ) and the half-time of the increase of K + concentration toward its stationary level (T 1/2 ) were measured under the control K (CK, 1% KCl) and high K (HK, 10% KCl) diets in the WT and TgWnk4 PHAII mice. The effects of Maxi-K channel inhibitor iberiotoxin were also measured under these conditions. Our experimental data show significantly elevated plasma K (PK) in TgWnk4 PHAII compared with WT mice. The PK was 5.35±0.36 vs. 4.43±0.19mEq/L in CK and was 6.60 ± 0.41 vs. 6.01±0.12 mEq/L (p<0.05) in HK-treated mice respectively. Q-PCR data show NCC expression was increased by 61% (p<0.05) and ROMK1 was reduced by 64% (p<0.05), ROMK2 was reduced 28% (P>0.05) respectively in (TgWnk4 PHAII ) compared with the WT. Micropuncture data show that the K + secretion was significantly reduced in the late distal tubule of the TgWnk4 PHAII mice compared with the WT under CK condition. The J K was reduced 47%; 0.137 ± 0.019 nmol/cm 2 /s vs. 0.261 ± 0.039 nmol/cm 2 /s (P< 0.05) and the T 1/2 increased 78%; 13.29 ± 1.19 vs. 23.65 ±2.28(s) (p<0.05) in TgWnk4 PHAII mice compared with the WT. Applying iberiotoxin (10 -7 M) in the tubular fluid did not change J K or T 1/2 in either WT or TgWnk4 PHAII mice, suggesting the Maxi-K channel does not contribute to distal tubule K + secretion under normal K conditions. Next, we treated animals with the HK diet for 7 days and the distal tubule K + secretion was remeasured. HK intake significantly increased K + secretion in the distal tubule in both WT and TgWnk4 PHAII mice. The J K was increased from 0.261 to 0.434 nmol/cm 2 /s (p<0.05) in WT and increased from 0.137 to 0.484 nmol/cm 2 /s (p<0.05), in TgWnk4 PHAII mice respectively. The increase in K + secretion by HK intake was completely abolished by the Maxi-K channel inhibitor iberiotoxin in both the WT and TgWnk4 PHAII mice. These data confirm that impaired K + secretion in the late distal tubule of TgWnk4 PHAII mice by reduced ROMK channel-mediated mechanism and the impaired distal tubule K + secretion was not compensated by Maxi-K channels in TgWnk4 PHAII mice under normal K condition. The PHAII-WNK4 mutation did not affect the HK-stimulated Maxi-K channel functions in the distal nephron. This work was supported by NIH grants R01 DK117650 and P01 DK 17433 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.