title: Sulfatides are required for renal adaptation to chronic metabolic acidosis.
abstract: Urinary ammonium excretion by the kidney is essential for renal excretion of sufficient amounts of protons and to maintain stable blood pH. Ammonium secretion by the collecting duct epithelia accounts for the majority of urinary ammonium; it is driven by an interstitium-to-lumen NH3 gradient due to the accumulation of ammonium in the medullary and papillary interstitium. Here, we demonstrate that sulfatides, highly charged anionic glycosphingolipids, are important for maintaining high papillary ammonium concentration and increased urinary acid elimination during metabolic acidosis. We disrupted sulfatide synthesis by a genetic approach along the entire renal tubule. Renal sulfatide-deficient mice had lower urinary pH accompanied by lower ammonium excretion. Upon acid diet, they showed impaired ammonuria, decreased ammonium accumulation in the papilla, and chronic hyperchloremic metabolic acidosis. Expression levels of ammoniagenic enzymes and Na(+)-K(+)/NH4(+)-2Cl(-) cotransporter 2 were higher, and transepithelial NH3 transport, examined by in vitro microperfusion of cortical and outer medullary collecting ducts, was unaffected in mutant mice. We therefore suggest that sulfatides act as counterions for interstitial ammonium facilitating its retention in the papilla. This study points to a seminal role of sulfatides in renal ammonium handling, urinary acidification, and acid-base homeostasis.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Stettner
authors.forename: Soline
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Christian
authors.initials: C
authors.lastname: Marsching
authors.forename: Milena
authors.initials: M
authors.lastname: Traykova-Brauch
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.forename: Viola
authors.initials: V
authors.lastname: Nordström
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Robert
authors.initials: R
authors.lastname: Koesters
authors.forename: Robert
authors.initials: R
authors.lastname: Kösters
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.forename: Herbert
authors.initials: H
authors.lastname: Wiegandt
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Richard
authors.initials: R
authors.lastname: Jennemann
mesh_terms: D000138:Acidosis / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D000641:Ammonia / Q000378:metabolism* / Q000652:urine; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005964:Glucosyltransferases / Q000172:deficiency / Q000235:genetics; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014556:Urine / Q000737:chemistry
chemical_list: D013433:Sulfoglycosphingolipids; D027981:Symporters; D000641:Ammonia; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D015238:Sulfotransferases; C020556:galactosylceramide sulfotransferase