Haploinsufficiency of the Mouse Atp6v1b1 Gene Leads to a Mild Acid-Base Disturbance with Implications for Kidney Stone Disease

Abstract

Background/Aims: Homozygous mutations or deletion of the ATP6V1B1 gene encoding for the B1 subunit of the vacuolar H⁺-ATPase leads to distal renal tubular acidosis in man and mice. In humans, heterozygous carriers of B1 mutations can develop incomplete dRTA with nephroclacinosis. Here, we investigated whether Atp6v1b1^+/- mice also develop acid-base disturbances during an HCl acid load. Methods: We subjected Atp6v1b1^+/+, Atp6v1b1^+/-, Atp6v1b1^-/- to an HCl-load for 7 days and investigated acid-base status, kidney function, and expression of renal acid-base transport proteins. Results: Atp6v1b1^-/- mice had more alkaline urine and low ammoniuria, whereas Atp6v1b1^+/- mice showed no difference in their urine parameters but higher blood chloride and lower blood pCO₂ compared to controls. Subcellular localization of a4 and B2 subunits of H⁺-ATPase were unchanged within the 3 genotypes and Atp6v1b1^+/+ and Atp6v1b1^+/- mice exhibited a similar luminal localization of B1 subunit in intercalated cells. However, B1, B2 and a4 expression were decreased in renal membrane fractions from Atp6v1b1^+/- mice compared to Atp6v1b1^+/+ while B2 and a4 were unchanged and B1 protein was reduced in Atp6v1b+^-/- kidneys. Compensatory mechanisms of B1 ablation were found only in the collecting duct with a down-regulation of pendrin in Atp6v1b1^-/- mice. Conclusions: In conclusion, 1) Atp6v1b1^+/- mice developed a mild incomplete dRTA. dRTA is partly compensated by respiration. 2) Compensatory mechanisms for the absence of B1 take place only in the collecting duct of Atp6v1b1^-/- kidneys.

The Renal Physiology of Pendrin-Positive Intercalated Cells

“…As collecting duct cells differentiate and mature, they acquire markers typical of either principal or intercalated cells. In the mouse, the H ϩ -ATPase appears at embryonic day 13 (E.13) (193), whereas pendrin-positive and AE1positive cells appear by E. 14. Throughout the remainder of gestation, pendrin-and AE1-positive cells increase in number (193).…”

“…Similarly, when quantified by immunoblot, pendrin total protein abundance increases following NaHCO 3 administration (46). Conversely, pendrin total protein abundance falls in rodent models associated with metabolic acidosis, such as following AE1 gene ablation (196), H ϩ -ATPase B1 (ATP6V1B1) subunit gene ablation (14), NH 4 ϩ administration (46,60,155,227), or following carbonic anhydrase inhibition (60). Lastly, pendrin abundance also falls in rodent models of respiratory acidosis (29).…”

Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020

“…11,18 This increase in apical plasma membrane pendrin abundance occurs more through pendrin subcellular redistribution than through changes in protein abundance. 11,18,43 Conversely, pendrin protein abundance falls in models of metabolic acidosis, as seen with either AE1 52 or the H + -ATPase B1 subunit (ATP6V1B1) 53 gene ablation or with the administration of NH 4 +43, 44,54,55 or a carbonic anhydrase inhibitor. 55 Since pendrin mediates HCO 3 − secretion, we hypothesized that in the absence of pendrin, arterial pH and HCO 3 − concentration will increase.…”

Incomplete distal renal tubular acidosis in children

“…Thus, the deletion of the Ncoa7 gene coding the nuclear receptor coactivator 7 reduced the abundance of several H+‐ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 in medullary intercalated cells of mouse kidneys and caused persistently high urine pH and hypobicarbonataemia after acid loading with NH4Cl 27 . Likewise, mice with haploinsufficiency of the Atp6v1b1 gene, coding the B subunit of the vacuolar H+‐ATPase, developed a mild iDRTA 28 …”