NYMC Faculty Publications
Renal Tubule Nedd4-2 Deficiency Stimulates Kir4.1/Kir5.1 and Thiazide-Sensitive NaCl Cotransporter in Distal Convoluted Tubule
DOI
10.1681/ASN.2019090923
Journal Title
Journal of the American Society of Nephrology
First Page
1226
Last Page
1242
Document Type
Article
Publication Date
6-2020
Department
Pharmacology
Keywords
Animals, Epithelial Sodium Channels, Kidney Tubules, Distal, Mice, Mice, Knockout, Nedd4 Ubiquitin Protein Ligases, Potassium Channels, Inwardly Rectifying, Sodium Chloride Symporters, Thiazides
Disciplines
Medicine and Health Sciences
Abstract
BACKGROUND: The potassium channel Kir4.1 forms the Kir4.1/Kir5.1 heterotetramer in the basolateral membrane of the distal convoluted tubule (DCT) and plays an important role in the regulation of the thiazide-sensitive NaCl cotransporter (NCC). Kidney-specific deletion of the ubiquitin ligase Nedd4-2 increases expression of NCC, and coexpression of Nedd4-2 inhibits Kir4.1/Kir5.1
METHODS: We used electrophysiology studies, immunoblotting, immunostaining, and renal clearance to examine Kir4.1/Kir5.1 activity in the DCT and NCC expression/activity in wild-type mice and mice with kidney-specific knockout of Nedd4-2, Kir4.1, or both.
RESULTS: Deletion of Nedd4-2 increased the activity/expression of Kir4.1 in the DCT and also, hyperpolarized the DCT membrane. Expression of phosphorylated NCC/total NCC and thiazide-induced natriuresis were significantly increased in the Nedd4-2 knockout mice, but these mice were normokalemic. Double-knockout mice lacking both Kir4.1/Kir5.1 and Nedd4-2 in the kidney exhibited increased expression of the epithelial sodium channel
CONCLUSIONS: Nedd4-2 regulates Kir4.1/Kir5.1 expression/activity in the DCT and modulates NCC expression by Kir4.1-dependent and Kir4.1-independent mechanisms. Basolateral Kir4.1/Kir5.1 activity in the DCT partially accounts for the stimulation of NCC activity/expression induced by deletion of Nedd4-2.
Recommended Citation
Wu, P., Su, X., Gao, Z., Zhang, D., Duan, X., Xiao, Y., Staub, O., Wang, W., & Lin, D. (2020). Renal Tubule Nedd4-2 Deficiency Stimulates Kir4.1/Kir5.1 and Thiazide-Sensitive NaCl Cotransporter in Distal Convoluted Tubule. Journal of the American Society of Nephrology, 31 (6), 1226-1242. https://doi.org/10.1681/ASN.2019090923
