title: Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption.
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.
authors.affiliation: From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 tpavlov@mcw.edu.
authors.forename: Tengis S
authors.initials: TS
authors.lastname: Pavlov
authors.affiliation: From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Levchenko
authors.affiliation: From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 staruschenko@mcw.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Staruschenko
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017136:Ion Transport; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D065608:Renal Reabsorption / Q000187:drug effects; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D017673:Sodium Chloride, Dietary; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D004815:Epidermal Growth Factor; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Epidermal Growth Factor (EGF); Epithelial Cell; Epithelial Sodium Channel (ENaC); Hypertension; Ion Channel; Kidney; Nephrology; Ras-related C3 Botulinum Toxin Substrate 1 (Rac1); Rho GTPases; Sodium Channel