The Rhesus factor protein, Rh C glycoprotein (Rhcg), is an ammonia transporter whose expression in the collecting duct is necessary for normal ammonia excretion both in basal conditions and in response to metabolic acidosis. Hypokalemia is a common clinical condition associated with increased renal ammonia excretion. In contrast to basal conditions and metabolic acidosis, increased ammonia excretion during hypokalemia can lead to an acid-base disorder, metabolic alkalosis, rather than maintenance of acid-base homeostasis. The purpose of the current studies was to determine Rhcg's role in hypokalemia-stimulated renal ammonia excretion through the use of mice with collecting duct-specific Rhcg deletion (CD-Rhcg-KO). In mice with intact Rhcg expression, a K+-free diet increased urinary ammonia excretion and urine alkalinization and concurrently increased Rhcg expression in the collecting duct in the outer medulla. Immunohistochemistry and immunogold electron microscopy showed hypokalemia increased both apical and basolateral Rhcg expression. In CD-Rhcg-KO, a K+-free diet increased urinary ammonia excretion and caused urine alkalinization, and the magnitude of these changes did not differ from mice with intact Rhcg expression. In mice on a K+-free diet, CD-Rhcg-KO increased phosphate-dependent glutaminase (PDG) expression in the outer medulla. We conclude that hypokalemia increases collecting duct Rhcg expression, that this likely contributes to the hypokalemia-stimulated increase in urinary ammonia excretion, and that adaptive increases in PDG expression can compensate for the absence of collecting duct Rhcg.
- Collecting duct