Mice disrupted for the ammonia channel RhCG compensate a physiological acid load of high protein diet

Ammonium (NH 4 + ) excretion in the urine is a critical mechanism by which the kidneys clear the excess of acid from the blood. A breakdown in this process leads to metabolic acidosis, as it was observed in HCl acid‐loaded mice harboring a deletion of the ammonia channel RhCG gene. Dietary intakes enriched in protein are known to induce an acid load in both human and rodents. We used here a high protein diet (HP) to investigate the response of Rhcg +/+, +/− and −/− mice exposed to a mild physiological acid load. Metabolic parameters of these animals treated for 9 days with HP diet revealed that after 4 days, Rhcg −/− excreted 30% less urinary NH 4 + than +/+, but at day 9, Rhcg −/− mice interestingly adapted fully to the diet, excreting as much NH 4 + as Rhcg +/+. The mRNA and protein expression of proteins involved in renal NH 4 + metabolism, SNAT3, PDG, and NKCC2 were enhanced in Rhcg +/− or −/− and both groups concentrated more NH 4 + in the inner medulla than Rhcg +/+, suggesting that these mice produce and reabsorb more NH 4 + to properly acidify urine after HP acid load. Finally, Rhcg −/− presented signs of bone degradation with hypercalcemia and hypercalciuria after 4 days of HP diet together with an increased release of deoxypiridinoline (a marker of bone resorption). Thus, Rhcg −/− and +/− mice handle a physiological HP acid load using specific adaptation mechanisms, however they cannot avoid bone degradation under these conditions. Supported by the Swiss National Science Foundation