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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents

ID: 723907.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na+-HCO3- Cotransporter Electrogenic 2 Deficiency
Authors:Wen, D.; Yuan, Y.; Warner, P. C.; Wang, B.; Cornelius, R. J.; Wang-France, J.; Li, H.; Boettger, T.; Sansom, S. C.
Date of Publication (YYYY-MM-DD):2015-07
Title of Journal:Hypertension
Issue / Number:1
Start Page:68
End Page:74
Audience:Not Specified
Abstract / Description:The gene SLC4A5 encodes the Na(+)-HCO3 (-) cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na(+)-HCO3 (-) cotransporter electrogenic 2 (knockout) causes Na(+)-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether overactive epithelial Na(+) channels (ENaC) or the Na(+)-Cl(-) cotransporter causes the Na(+) retention and hypertension in knockout. In untreated mice, the mean arterial pressure was higher in knockout, compared with wild-type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide, an inhibitor of Na(+)-Cl(-) cotransporter, decreased mean arterial pressure in WT, but not knockout. Western blots showed that quantity of plasmalemmal full-length ENaC-alpha was significantly higher in knockout than in WT. Amiloride treatment caused a 2-fold greater increase in Na(+) excretion in knockout, compared with WT. In knockout, but not WT, amiloride treatment decreased plasma [Na(+)] and urinary K(+) excretion, but increased hematocrit and plasma [K(+)] significantly. Micropuncture with microelectrodes showed that the [K(+)] was significantly higher and the transepithelial potential (Vte) was significantly lower in the late distal tubule of the knockout compared with WT. The reduced Vte in knockout was amiloride sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na(+) reabsorption in this segment. These results show that, in the absence of Na(+)-HCO3 (-) cotransporter electrogenic 2 in the late distal tubule, acid-loaded mice exhibit disinhibition of ENaC-mediated Na(+) reabsorption, which results in Na(+) retention, K(+) wasting, and hypertension.
Free Keywords:Amiloride/pharmacology/therapeutic use; Animals; Antihypertensive Agents/therapeutic use; Disease Models, Animal; Diuretics/therapeutic use; Epithelial Sodium Channels/drug effects/*physiology; Hematocrit; Hydrochlorothiazide/therapeutic use; Hydrogen-Ion Concentration; Hypertension, Renal/drug therapy/genetics/*metabolism; Hypokalemia/etiology; Kidney Tubules, Distal/metabolism; Membrane Potentials/drug effects; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Natriuresis/drug effects/genetics; Polymorphism, Single Nucleotide; Potassium/metabolism; Sodium/metabolism; Sodium Channel Blockers/pharmacology/therapeutic use; Sodium-Bicarbonate Symporters/*deficiency/genetics/physiology; NBCe2 protein; epithelial Na+ channel blockers; hypertension; punctures
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (D.W., Y.Y., P.C.W., B.W., R.J.C., J.W.-F., H.L., S.C.S.); and Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.). ssansom@unmc.edu.
Identifiers:ISSN:1524-4563 (Electronic) 0194-911X (Linking) %R 10.1161/HYPERTENSIONAHA.115.05394
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