title: Reducing αENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading.
abstract: Genetic inactivation of the epithelial Na(+) channel α-subunit (αENaC) in the renal collecting duct (CD) does not interfere with Na(+) and K(+) homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of αENaC in the CNT. Knockout mice with αENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1a(lox/lox) mice and Atp6v1b1::Cre mice. With a standard diet, plasma Na(+) concentration ([Na(+)]) and [K(+)], and urine Na(+) and K(+) output were unaffected. Seven days of Na(+) restriction (0.01% Na(+)) led to a higher urine Na(+) output only on days 3-5, and after 7 days plasma [Na(+)] and [K(+)] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K(+) diet and showed lower food intake and relative body weight, lower plasma [Na(+)], higher fractional excretion (FE) of Na(+), higher plasma [K(+)], and lower FE of K(+). The higher FE of Na(+) coincided with lower abundance and phosphorylation of the Na(+)-Cl(-) cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K(+) loading.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark;
authors.forename: Søren Brandt
authors.initials: SB
authors.lastname: Poulsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark;
authors.forename: Jeppe
authors.initials: J
authors.lastname: Praetorius
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Helle H
authors.initials: HH
authors.lastname: Damkier
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
authors.forename: Lance
authors.initials: L
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
authors.forename: Raoul D
authors.initials: RD
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; bmc@biomed.au.dk.
authors.forename: Birgitte Mønster
authors.initials: BM
authors.lastname: Christensen
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D003106:Colon / Q000378:metabolism; D004032:Diet; D004435:Eating; D053503:Epithelial Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D007685:Kidney Tubules, Collecting / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011188:Potassium / Q000097:blood / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000097:blood / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000096:biosynthesis / Q000235:genetics; D064486:Solute Carrier Family 12, Member 3 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; C578715:Slc12a1 protein, mouse; C578875:Slc12a3 protein, mouse; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D000450:Aldosterone; D012964:Sodium; D011188:Potassium
keywords: aldosterone; kidney connecting tubule; potassium; sodium; αENaC