The B1-subunit of the H⁺ATPase is required for maximal urinary acidification

Abstract

The multisubunit vacuolar-type H ؉ ATPases mediate acidification of various intracellular organelles and in some tissues mediate H ؉ secretion across the plasma membrane. Mutations in the B1-subunit of the apical H ؉ ATPase that secretes protons in the distal nephron cause distal renal tubular acidosis in humans, a condition characterized by metabolic acidosis with an inappropriately alkaline urine. To examine the detailed cellular and organismal physiology resulting from this mutation, we have generated mice deficient in the B1-subunit (Atp6v1b1 ؊/؊ mice). Urine pH is more alkaline and metabolic acidosis is more severe in Atp6v1b1 ؊/؊ mice after oral acid challenge, demonstrating a failure of normal urinary acidification. In Atp6v1b1 ؊/؊ mice, the normal urinary acidification induced by a lumen-negative potential in response to furosemide infusion is abolished. After an acute intracellular acidification, Na ؉ -independent pH recovery rates of individual Atp6v1b1 ؊/؊ intercalated cells of the cortical collecting duct are markedly reduced and show no further decrease after treatment with the selective H ؉ ATPase inhibitor concanamycin. Apical expression of the alternative B-subunit isoform, B2, is increased in Atp6v1b1 ؊/؊ medulla and colocalizes with the H ؉ ATPase E-subunit; however, the greater severity of metabolic acidosis in Atp6v1b1 ؊/؊ mice after oral acid challenge indicates that the B2-subunit cannot fully functionally compensate for the loss of B1. Our results indicate that the B1 isoform is the major B-subunit isoform that incorporates into functional, plasma membrane H ؉ ATPases in intercalated cells of the cortical collecting duct and is required for maximal urinary acidification.collecting duct ͉ intercalated cell ͉ pH homeostasis ͉ renal tubular acidosis ͉ vacuolar H ϩ ATPase

The Calcium-Sensing Receptor Promotes Urinary Acidification to Prevent Nephrolithiasis

“…37,38 Atp6v1b1 Ϫ/Ϫ mice demonstrated hypocalciuria, which is an important difference in phenotype between mice and humans with a genetic Atp6v1b1 defect, although it confirms previous observations of Finberg et al 38 The presence of hypocalciuria in Atp6v1b1 Ϫ/Ϫ has not been explained yet and needs further investigation. Moreover, Atp6v1b1…”

“…38 Consequently, gene ablation of the Atp6v1b1 gene in TRPV5 Ϫ/Ϫ mice normalized urinary pH. Interestingly, TRPV5…”

Vacuolar H+-ATPase B1 Subunit Mutations that Cause Inherited Distal Renal Tubular Acidosis Affect Proton Pump Assembly and Trafficking in Inner Medullary Collecting Duct Cells

“…If this is the case, then one would predict that Atp6v1b1 Ϫ/Ϫ animals should have a similar phenotype. Surprising, Atp6v1b1 Ϫ/Ϫ mice seem healthy, grow normally, do not have hearing defects, and are without systemic metabolic acidosis when on a normal diet and develop acidosis only when challenged (22,23). It is interesting that a recent study indicated that the absence of B1 expression induces a compensatory increase of the B2 isoform that potentially may act as a substitute isoform for B1 to increase H ϩ -ATPase activity in these Atp6v1b1 Ϫ/Ϫ mice (23).…”

Role of the Calcium-Sensing Receptor in Reducing the Risk for Calcium Stones

“…In 2009, we described how the exposure to high (5.0 mM) Ca 2ϩ concentrations significantly enhanced H ϩ -ATPase activity in CD cells (32). This stimulatory effect was absent in CD cells from Atp6v1b1 knockout mice that were genetically ablated for the CD-specific B1 subunit of H ϩ -ATPase (35). Moreover, the CaSR agonist neomycin increased H ϩ -ATPase activity as well, indicating the modulation of urinary acid excretion by CaSR activation.…”