Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins.
Chronic metabolic acidosis results in renal Ca2+ and Mg2+ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca2+ and Mg2+ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca2+ channel TRPV5, the Ca2+-binding protein calbindin-D28K, and the epithelial Mg2+ channel TRPM6 in relation to Ca2+ and Mg2+ excretion. Chronic metabolic acidosis that was induced by NH4Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca2+ excretion in TRPV5 knockout (TRPV5-/-) mice, in which active Ca2+ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca2+ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO3 administration for 6 d increased the expression of Ca2+ transport proteins accompanied by diminished urine Ca2+ excretion in wild-type mice. However, this Ca2+-sparing action persisted in TRPV5-/- mice, suggesting that additional mechanisms apart from upregulation of active Ca2+ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg2+ excretion, and decreased serum Mg2+ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca2+ and Mg2+ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.
Nijenhuis
Tom
T
Department of Physiology, Radboud University Nijmegen Medical Centre, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.
Renkema
Kirsten Y
KY
Hoenderop
Joost G J
JG
Bindels
René J M
RJ
D000138:Acidosis / Q000378:metabolism / Q000503:physiopathology*; D000471:Alkalosis / Q000378:metabolism / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015151:Immunoblotting; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011336:Probability; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D016482:Urinalysis
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D008274:Magnesium