Faculty Collaboration Database

Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption. J Biol Chem 2014 Oct 10;289(41):28651-9

Date

08/29/2014

Pubmed ID

25164814

Pubmed Central ID

PMC4192514

DOI

10.1074/jbc.M114.558262

Scopus ID

2-s2.0-84907646378 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

The epithelial sodium channel (ENaC) is expressed in the aldosterone-sensitive distal nephron where it performs sodium reabsorption from the lumen. We have recently shown that ENaC activity contributes to the development of salt-induced hypertension as a result of deficiency of EGF level. Previous studies revealed that Rho GDP-dissociation inhibitor α (RhoGDIα) is involved in the control of salt-sensitive hypertension and renal injury via Rac1, which is one of the small GTPases activating ENaC. Here we investigated the intracellular mechanism mediating the involvement of the RhoGDIα/Rac1 axis in the control of ENaC and the effect of EGF on ENaC in this pathway. We demonstrated that RhoGDIα is highly expressed in the cortical collecting ducts of mice and rats, and its expression is down-regulated in Dahl salt-sensitive rats fed a high salt diet. Knockdown of RhoGDIα in cultured cortical collecting duct principal cells increased ENaC subunits expression and ENaC-mediated sodium reabsorption. Furthermore, RhoGDIα deficiency causes enhanced response to EGF treatment. Patch clamp analysis reveals that RhoGDIα significantly decreases ENaC current density and prevents its up-regulation by RhoA and Rac1. Inhibition of Rho kinase with Y27632 had no effects on ENaC response to EGF either in control or RhoGDIα knocked down cells. However, EGF treatment increased levels of active Rac1, which was further enhanced in RhoGDIα-deficient cells. We conclude that changes in the RhoGDIα-dependent pathway have a permissive role in the Rac1-mediated enhancement of ENaC activity observed in salt-induced hypertension.

Author List

Pavlov TS, Levchenko V, Staruschenko A

MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Epidermal Growth Factor
Epithelial Cells
Epithelial Sodium Channels
Gene Expression Regulation
Hypertension
Ion Transport
Kidney Tubules, Collecting
Membrane Potentials
Mice
Mice, Inbred C57BL
Neuropeptides
Patch-Clamp Techniques
RNA, Small Interfering
Rats
Rats, Inbred Dahl
Renal Reabsorption
Signal Transduction
Sodium Chloride, Dietary
rac1 GTP-Binding Protein
rho Guanine Nucleotide Dissociation Inhibitor alpha