title: Haploinsufficiency of the ammonia transporter Rhcg predisposes to chronic acidosis: Rhcg is critical for apical and basolateral ammonia transport in the mouse collecting duct.
abstract: Ammonia secretion by the collecting duct (CD) is critical for acid-base homeostasis and, when defective, causes distal renal tubular acidosis (dRTA). The Rhesus protein RhCG mediates NH(3) transport as evident from cell-free and cellular models as well as from Rhcg-null mice. Here, we investigated in a Rhcg mouse model the metabolic effects of Rhcg haploinsufficiency, the role of Rhcg in basolateral NH(3) transport, and the mechanisms of adaptation to the lack of Rhcg. Both Rhcg(+/+) and Rhcg(+/-) mice were able to handle an acute acid load, whereas Rhcg(-/-) mice developed severe metabolic acidosis with reduced ammonuria and high mortality. However, chronic acid loading revealed that Rhcg(+/-) mice did not fully recover, showing lower blood HCO(3)(-) concentration and more alkaline urine. Microperfusion studies demonstrated that transepithelial NH(3) permeability was reduced by 80 and 40%, respectively, in CDs from Rhcg(-/-) and Rhcg(+/-) mice compared with controls. Basolateral membrane permeability to NH(3) was reduced in CDs from Rhcg(-/-) mice consistent with basolateral Rhcg localization. Rhcg(-/-) responded to acid loading with normal expression of enzymes and transporters involved in proximal tubular ammoniagenesis but reduced abundance of the NKCC2 transporter responsible for medullary accumulation of ammonium. Consequently, tissue ammonium content was decreased. These data demonstrate a role for apical and basolateral Rhcg in transepithelial NH(3) transport and uncover an incomplete dRTA phenotype in Rhcg(+/-) mice. Haploinsufficiency or reduced expression of RhCG may underlie human forms of (in)complete dRTA.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Soline
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Lisa
authors.initials: L
authors.lastname: Bounoure
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006720:Homozygote; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype
chemical_list: D027682:Cation Transport Proteins; D008562:Membrane Glycoproteins; C485880:Rhcg protein, mouse; D000641:Ammonia