Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat.
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.
Ambühl
P M
PM
Department of Medicine, University of Texas, Southwestern Medical Center at Dallas, USA.
Zajicek
H K
HK
Wang
H
H
Puttaparthi
K
K
Levi
M
M
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
D001639:Bicarbonates; D002352:Carrier Proteins; D008563:Membrane Lipids; D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters