Federica Rizzo1, Olivier Staub. 1. Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Abstract
PURPOSE OF REVIEW: NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's syndrome, causing elevated ENaC activity and salt-sensitive hypertension. In this review we aim to highlight progress achieved in recent years demonstrating that NEDD4-2 is involved in the control of Na+ transporters that are different from ENaC, but which also play a role in salt-sensitive hypertension. RECENT FINDINGS: It has been shown that NEDD4-2 interacts with ubiquitylates and negatively regulates the thiazide-sensitive NCC (Na+,Cl- -cotransporter), both in vitro and in vivo in inducible, nephron-specific Nedd4-2 knockout mice. Moreover, evidence has been provided that NEDD4-2 is also involved in the regulation of human NHE3 (Na+,H+-exchanger 3) and NKCC2 (Na+,K+,2Cl- -cotransporter 2). SUMMARY: The emerging role of NEDD4-2 in the regulation of different Na+ transporters along the nephron and the identification of human polymorphisms in the NEDD4-2 gene (Nedd4L) related to salt-sensitive hypertension makes this ubiquitin-protein ligase an interesting target for the development of antihypertensive drugs.
PURPOSE OF REVIEW: NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's syndrome, causing elevated ENaC activity and salt-sensitive hypertension. In this review we aim to highlight progress achieved in recent years demonstrating that NEDD4-2 is involved in the control of Na+ transporters that are different from ENaC, but which also play a role in salt-sensitive hypertension. RECENT FINDINGS: It has been shown that NEDD4-2 interacts with ubiquitylates and negatively regulates the thiazide-sensitive NCC (Na+,Cl- -cotransporter), both in vitro and in vivo in inducible, nephron-specific Nedd4-2 knockout mice. Moreover, evidence has been provided that NEDD4-2 is also involved in the regulation of humanNHE3 (Na+,H+-exchanger 3) and NKCC2 (Na+,K+,2Cl- -cotransporter 2). SUMMARY: The emerging role of NEDD4-2 in the regulation of different Na+ transporters along the nephron and the identification of human polymorphisms in the NEDD4-2 gene (Nedd4L) related to salt-sensitive hypertension makes this ubiquitin-protein ligase an interesting target for the development of antihypertensive drugs.
Authors: Callie P Wigington; Jagoree Roy; Nikhil P Damle; Vikash K Yadav; Cecilia Blikstad; Eduard Resch; Cassandra J Wong; Douglas R Mackay; Jennifer T Wang; Izabella Krystkowiak; Devin A Bradburn; Eirini Tsekitsidou; Su Hyun Hong; Malika Amyn Kaderali; Shou-Ling Xu; Tim Stearns; Anne-Claude Gingras; Katharine S Ullman; Ylva Ivarsson; Norman E Davey; Martha S Cyert Journal: Mol Cell Date: 2020-07-08 Impact factor: 17.970
Authors: Mohammed Z Ferdaus; Anindit Mukherjee; Jonathan W Nelson; Philip J Blatt; Lauren N Miller; Andrew S Terker; Olivier Staub; Dao-Hong Lin; James A McCormick Journal: Am J Physiol Renal Physiol Date: 2019-07-31