title: Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and glycosphingolipid composition.
abstract: Glucocorticoids are important regulators of renal phosphate transport. This study investigates the role of alterations in renal brush border membrane (BBM) sodium gradient-dependent phosphate transport (Na-Pi cotransporter) mRNA and protein abundance in the dexamethasone induced inhibition of Na-Pi cotransport in the rat. Dexamethasone administration for 4 d caused a 1.5-fold increase in the Vmax of Na-Pi cotransport (1785 +/- 119 vs. 2759 +/- 375 pmol/5 s per mg BBM protein in control, P < 0.01), which was paralleled by a 2.5-fold decrease in the abundance of Na-Pi mRNA and Na-Pi protein. There was also a 1.7-fold increase in BBM glucosylceramide content (528 +/- 63 vs. 312 +/- 41 ng/mg BBM protein in control, P < 0.02). To determine whether the alteration in glucosylceramide content per se played a functional role in the decrease in Na-Pi cotransport, control rats were treated with the glucosylceramide synthase inhibitor, D-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol (PDMP). The resultant 1.5-fold decrease in BBM glucosylceramide content (199 +/- 19 vs. 312 +/- 41 ng/mg BBM protein in control, P < 0.02) was associated with a 1.4-fold increase in Na-Pi cotransport activity (1422 +/- 73 vs. 1048 +/- 85 pmol/5 s per mg BBM protein in control, P < 0.01), and a 1.5-fold increase in BBM Na-Pi protein abundance. Thus, dexamethasone-induced inhibition of Na-Pi cotransport is associated with a decrease in BBM Na-Pi cotransporter abundance, and an increase in glucosylceramide. Since primary alteration in BBM glucosylceramide content per se directly and selectively modulates BBM Na-Pi cotransport activity and Na-Pi protein abundance, we propose that the increase in BBM glucosylceramide content plays an important role in mediating the inhibitory effect of dexamethasone on Na-Pi cotransport activity.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: J A
authors.initials: JA
authors.lastname: Shayman
authors.forename: A
authors.initials: A
authors.lastname: Abe
authors.forename: S K
authors.initials: SK
authors.lastname: Gross
authors.forename: R H
authors.initials: RH
authors.lastname: McCluer
authors.forename: J
authors.initials: J
authors.lastname: Biber
authors.forename: H
authors.initials: H
authors.lastname: Murer
authors.forename: M
authors.initials: M
authors.lastname: Lötscher
authors.forename: R E
authors.initials: RE
authors.lastname: Cronin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D006028:Glycosphingolipids / Q000032:analysis*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D010710:Phosphates / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D006028:Glycosphingolipids; D028044:Phosphate-Binding Proteins; D010710:Phosphates; D012333:RNA, Messenger; D003907:Dexamethasone; D012964:Sodium