Effects of chronic hypercapnia on ammonium transport in the mouse kidney

Hypercapnia and subsequent respiratory acidosis are serious complications in many patients with respiratory disorders. The acute response to hypercapnia is buffering of H(+) by hemoglobin and cellular proteins but this effect is limited. The chronic response is renal compensation that increases HCO(3) (−) reabsorption, and stimulates urinary excretion of titratable acids (TA) and NH(4) (+). However, the main effective pathway is the excretion of NH(4) (+) in the collecting duct. Our hypothesis is that, the renal NH(3)/NH(4) (+) transporters, Rhbg and Rhcg, in the collecting duct mediate this response. The effect of hypercapnia on these transporters is unknown. We conducted in vivo experiments on mice subjected to chronic hypercapnia. One group breathed 8% CO(2) and the other breathed normal air as control (0.04% CO(2)). After 3 days, the mice were euthanized and kidneys, blood, and urine samples were collected. We used immunohistochemistry and Western blot analysis to determine the effects of high CO(2) on localization and expression of the Rh proteins, carbonic anhydrase IV, and pendrin. In hypercapnic animals, there was a significant increase in urinary NH(4) (+) excretion but no change in TA. Western blot analysis showed a significant increase in cortical expression of Rhbg (43%) but not of Rhcg. Expression of CA‐IV was increased but pendrin was reduced. These data suggest that hypercapnia leads to compensatory upregulation of Rhbg that contributes to excretion of NH(3)/NH(4) (+) in the kidney. These studies are the first to show a link among hypercapnia, NH(4) (+) excretion, and Rh expression.