title: Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat.
abstract: Metabolic acidosis results in impaired renal tubular phosphate reabsorption and proximal tubular apical brush border membrane (BBM) sodium gradient-dependent phosphate transport (Na/Pi cotransport) activity. In the present study we investigated the cellular mechanisms responsible for decreased Na/Pi cotransport activity following six hours to 10 days of metabolic acidosis induced by ingestion of NH4Cl. Urinary Pi excretion was significantly increased and BBM Na/Pi cotransport activity was progressively and significantly decreased by 18% at six hours, 24% at 12 hours, 32% at 24 hours, and 61% after 10 days of metabolic acidosis. The progressive and time-dependent decreases in BBM cotransport activity were associated with progressive decreases in BBM NaPi-2 protein (43% at 12 hr, 54% at 24 hr and 66% at 10 days) and cortical NaPi-2 mRNA (22% at 12 hr, 54% at 24 hr and 56% at 10 days) abundance. Interestingly, following six hours of metabolic acidosis, there was a significant 29% decrease in BBM NaPi-2 protein abundance that was not associated with decreases in either cortical homogenate NaPi-2 protein or cortical NaPi-2 mRNA abundance. In additional studies we found that the effects of chronic metabolic acidosis on Na/Pi cotransport activity were independent of endogenous parathyroid hormone activity, but were somewhat dependent on dietary Pi intake. In rats fed a high or a normal Pi diet metabolic acidosis caused significant decreases in Na/Pi cotransport activity, NaPi-2 protein and NaPi-2 mRNA abundance, however, in rats fed a low Pi diet the inhibitory effect of metabolic acidosis on Na/Pi cotransport were minimal and not significant. These results indicate that in chronic (> or = 12 hr) metabolic acidosis the progressive decrease in BBM Na/Pi cotransport activity is most likely mediated by decrease in BBM NaPi-2 protein and cortical mRNA abundance. In contrast, in acute (< or = 6 hr) metabolic acidosis the decrease in BBM Na/Pi cotransport activity is likely mediated by changes in the trafficking of the NaPi-2 protein that is, enhanced internalization from and/or impaired delivery of the NaPi-2 protein to the apical BBM.
authors.affiliation: Department of Medicine, University of Texas, Southwestern Medical Center at Dallas, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Ambühl
authors.forename: H K
authors.initials: HK
authors.lastname: Zajicek
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Puttaparthi
authors.forename: M
authors.initials: M
authors.lastname: Levi
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism* / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters
chemical_list: D001639:Bicarbonates; D002352:Carrier Proteins; D008563:Membrane Lipids; D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters