We used whole cell recording to examine the renal outer medullary Kchannel (ROMK or Kir1.1) and epithelial Nachannel (ENaC) in the late distal convoluted tubule (DCT2)/initial connecting tubule (CNT) and in the cortical collecting duct (CCD) of kidney tubule-specific neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) knockout mice (Ks-Nedd4-2 KO) and floxed neural precursor cell-expressed developmentally downregulated 4-like () mice (control). Tertiapin Q (TPNQ)-sensitive Kcurrents (ROMK) were smaller in both the DCT2/CNT and CCD of Ks-Nedd4-2 KO mice on a normal diet than in control mice. Neither high dietary salt intake nor low dietary salt intake had a significant effect on ROMK activity in the DCT2/CNT and CCD of control and Ks-Nedd4-2 KO mice. In contrast, high dietary Kintake (HK) increased, whereas low dietary Kintake (LK) decreased TPNQ-sensitive Kcurrents in floxedmice. However, the effects of dietary Kintake on ROMK channel activity were absent in Ks-Nedd4-2 KO mice since neither HK nor LK significantly affected TPNQ-sensitive Kcurrents in the DCT2/CNT and CCD. Moreover, TPNQ-sensitive Kcurrents in the DCT2/CNT and CCD of Ks-Nedd4-2 KO mice on HK were similar to those of control mice on LK. Amiloride-sensitive Nacurrents in the DCT2/CNT and CCD were significantly higher in Ks-Nedd4-2 KO mice than in floxedmice on a normal Kdiet. HK increased ENaC activity of the DCT2/CNT only in control mice, but HK stimulated ENaC of the CCD in both control and Ks-Nedd4-2 KO mice. Moreover, the HK-induced increase in amiloride-sensitive Nacurrents was larger in Ks-Nedd4-2 KO mice than in control mice. Deletion of Nedd4-2 increased with no lysine kinase 1 expression and abolished HK-induced inhibition of with no lysine kinase 1. We conclude that deletion of Nedd4-2 increases ENaC activity but decreases ROMK activity in the aldosterone-sensitive distal nephron and that HK fails to stimulate ROMK, but robustly increases ENaC activity in the CCD of Nedd4-2-deficient mice.We demonstrate that renal outer medullary K(ROMK) channel activity is inhibited in the late distal convoluted tubule/initial connecting tubule and cortical collecting duct of neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2)-deficient mice. Also, deletion of Nedd4-2 abolishes the stimulatory effect of dietary Kintake on ROMK. The lack of high K-induced stimulation of ROMK is associated with the absence of high K-induced inhibition of with no lysine kinase 1. + + + + + + + + + + + + + + + + i i i i i i i Nedd4l Nedd4l Nedd4l NEW & NOTEWORTHY
