Impaired Urinary Concentration in Car2 Deficient Mice

Pharmacological inhibition of carbonic anhydrases and deficiency of carbonic anhydrase II (Car2) in mice cause polyuria. We therefore set out to determine in Car2 deficient mice by which mechanism(s) polyuria is mediated. Blood gas analysis revealed that Car2 deficient mice have a respiratory acidosis, as reported previously. Moreover, the acidotic mice failed to excrete an acidic urine and had significant bicarbonaturia, consistent with a type III renal tubular acidosis. Carbonic anhydrase inhibitors induce a natriuresis, however Car2 deficient mice did not have altered urinary sodium excretion (either total excretion or FE Na ). Deletion of NHE3 in mice results in calciuria, and inhibition of NHE3 in cell culture reduces transepithelial calcium flux. Carbonic anhydrase II enhances NHE3 activity and calciuria induces polyuria. However, Car2 deficient mice do not demonstrate altered urinary calcium excretion. Further examination revealed a dilute urine in Car2 deficient mice. Urinary concentration remained reduced in Car2 deficient mice relative to wild‐type animals even after water deprivation. Expression of aquaporin‐2 was not different between genotypes, however Car2‐deficient mice had increased renal aquaporin‐1 expression. Carbonic anhydrase II associates with and increases water flux through aquyaporin‐1. Water flux through aquaporin‐1 in the thin descending limb (TDL) of the loop of Henle is essential to the concentration of urine, by generating a concentrated medullary interstitium. Car2 is expressed in the thin descending limb. We therefore measured cortical and medullary interstitial concentration in wild‐type and Car2 deficient mice. Mice lacking Car2 had equivalent cortical interstitial osmolarity to WT mice however, they had a reduced medullary interstitial osmolarity. We propose that reduced water flux through aquaporin‐1 in the TDL in the absence of Car2 prevents the generation of a maximally concentrated medullary interstitium and thus the maximal concentration of urine in Car2 deficient mice resulting in polyuria. Support or Funding Information Canadian Institutes of Health Research