Lee HW, Verlander JW, Bishop JM, Handlogten ME, Han KH, Weiner ID. Renal ammonia excretion in response to hypokalemia: effect of collecting duct-specific Rh C glycoprotein deletion. Am J Physiol Renal Physiol 304: F410 -F421, 2013. First published December 5, 2012; doi:10.1152/ajprenal.00300.2012.-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 ϩ -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 ϩ -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 ϩ -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.acid-base; ammonia; collecting duct; hypokalemia; potassium RENAL AMMONIA METABOLISM is a primary method through which the kidneys maintain acid-base homeostasis, and involves integrated contributions of both intrarenal ammoniagenesis and renal epithelial cell ammonia transport.1 Increasingly, the "traditional" theory of passive NH 3 diffusion and NH 4 ϩ trapping is being replaced by one in which specific membrane proteins transport NH 3 or NH 4 ϩ , enabling facilitated and regulated membrane NH 3 and NH 4 ϩ transport (32, 33). Prominent among these ammonia-transporting proteins are the Rh glycoproteins. Three mammalian Rh glycoproteins have been identified, Rh A glycoprotein, which is expressed specifically in erythroid cells, and the nonerythroid Rh glycoproteins, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg), which are expressed widely in ammonia-transporting tissues, including the kidney (29,30,32,33).In the kidney, Rhcg is expressed in the renal distal nephron and collecting duct, from the distal convoluted tubule (DCT) through the inner medullary collecting duct (8,10,20,28), where 60 -80% of final...