Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption.
During metabolic acidosis (MA), urinary phosphate excretion increases and contributes to acid removal. Two Na(+)-dependent phosphate transporters, NaPi-IIa (Slc34a1) and NaPi-IIc (Slc34a3), are located in the brush border membrane (BBM) of the proximal tubule and mediate renal phosphate reabsorption. Transcriptome analysis of kidneys from acid-loaded mice revealed a large decrease in NaPi-IIc messenger RNA (mRNA) and a smaller reduction in NaPi-IIa mRNA abundance. To investigate the contribution of transporter regulation to phosphaturia during MA, we examined renal phosphate transporters in normal and Slc34a1-gene ablated (NaPi-IIa KO) mice acid-loaded for 2 and 7 days. In normal mice, urinary phosphate excretion was transiently increased after 2 days of acid loading, whereas no change was found in Slc34a1-/- mice. BBM Na/Pi cotransport activity was progressively and significantly decreased in acid-loaded KO mice, whereas in WT animals, a small increase after 2 days of treatment was seen. Acidosis increased BBM NaPi-IIa abundance in WT mice and NaPi-IIc abundance in WT and KO animals. mRNA abundance of NaPi-IIa and NaPi-IIc decreased during MA. Immunohistochemistry did not indicate any change in the localization of NaPi-IIa and NaPi-IIc along the nephron. Interestingly, mRNA abundance of both Slc20 phosphate transporters, Pit1 and Pit2, was elevated after 7 days of MA in normal and KO mice. These data demonstrate that phosphaturia during acidosis is not caused by reduced protein expression of the major Na/Pi cotransporters NaPi-IIa and NaPi-IIc and suggest a direct inhibitory effect of low pH mainly on NaPi-IIa. Our data also suggest that Pit1 and Pit2 transporters may play a compensatory role.
Nowik
Marta
M
Institute of Physiology and Zurich Center for Human Integrative Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Picard
Nicolas
N
Stange
Gerti
G
Capuano
Paola
P
Tenenhouse
Harriet S
HS
Biber
Jürg
J
Murer
Heini
H
Wagner
Carsten A
CA
D000138:Acidosis / Q000150:complications* / Q000652:urine; D000818:Animals; D004195:Disease Models, Animal; D006863:Hydrogen-Ion Concentration; D007015:Hypophosphatemia, Familial / Q000209:etiology* / Q000652:urine; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008871:Microvilli / Q000378:metabolism; D010710:Phosphates / Q000652:urine*; D012333:RNA, Messenger / Q000378:metabolism; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000378:metabolism; D013997:Time Factors
D010710:Phosphates; D012333:RNA, Messenger; C493587:Slc20a1 protein, mouse; C493565:Slc20a2 protein, mouse; C493555:Slc34a1 protein, mouse; C493563:Slc34a3 protein, mouse; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc