ENaC and ROMK activity are inhibited in the DCT2/CNT of TgWnk4^PHAII mice.

Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4^PHAII) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl cotransporter (NCC). This leads to decreasing Na⁺ delivery to the distal nephron segment including late distal convoluted tubule (DCT) and connecting tubule (CNT). Since epithelial Na⁺ channel (ENaC) and renal outer medullary K⁺ channel (ROMK or Kir4.1) are expressed in the late DCT and play an important role in mediating K⁺ secretion, the aim of the present study is to test whether ROMK and ENaC activity in the DCT/CNT are also compromised in the mice expressing PHAII mutant Wnk4. Western blot analysis shows that the expression of βENaC and γENaC subunits but not αENaC subunit was lower in TgWnk4^PHAII mice than that in wild-type (WT) and TgWnk4^WT mice. Patch-clamp experiments detected amiloride-sensitive Na⁺ currents and TPNQ-sensitive K⁺ currents in DCT2/CNT, suggesting the activity of ENaC and ROMK. However, both Na⁺ and ROMK currents in DCT2/CNT of TgWnk4^PHAII mice were significantly smaller than those in WT and TgWnk4^WT mice. In contrast, the basolateral K⁺ currents in the DCT were similar among three groups, despite higher NCC expression in TgWnk4^PHAII mice than those of WT and TgWnk4^WTmice. An increase in dietary K⁺ intake significantly increased both ENaC and ROMK currents in the DCT2/CNT of all three groups. However, high-K⁺ (HK) intake-induced stimulation of Na⁺ and K⁺ currents was smaller in TgWnk4^PHAII mice than those in WT and TgWnk4^WT mice. We conclude that ENaC and ROMK channel activity in DCT2/CNT are inhibited in TgWnk4^PHAII mice and that Wnk4^PHAII-induced inhibition of ENaC and ROMK may contribute to the suppression of K⁺ secretion in the DCT2/CNT in addition to increased NCC activity. Copyright © 2017 the American Physiological Society.

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