# Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation

## TL;DR

This review discusses how NKCC2 protein quality control in the ER affects Bartter syndrome and blood pressure regulation.

## Contribution

The paper summarizes recent findings on molecular determinants of NKCC2 export from the ER and its implications.

## Key findings

- ER retention and ERAD mechanisms prevent NKCC2 from reaching the plasma membrane in severe Bartter syndrome.
- Protein quality control at the ER is a critical step in NKCC2 maturation and trafficking.
- NKCC2 regulation is linked to both salt-sensitive hypertension and prenatal Bartter syndrome.

## Abstract

Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter’s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.