Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and glycosphingolipid composition.
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.
Levi
M
M
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, USA.
Shayman
J A
JA
Abe
A
A
Gross
S K
SK
McCluer
R H
RH
Biber
J
J
Murer
H
H
Lötscher
M
M
Cronin
R E
RE
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
D002352:Carrier Proteins; D006028:Glycosphingolipids; D028044:Phosphate-Binding Proteins; D010710:Phosphates; D012333:RNA, Messenger; D003907:Dexamethasone; D012964:Sodium