Increased sensitivity to K⁺ deprivation in colonic H,K-ATPase-deficient mice

Previous studies using isolated tissues suggest that the colonic H,K- ATPase (cHKA), expressed in the colon and kidney, plays an important role in K⁺ conservation. To test the role of this pump in K⁺ homeostasis in vivo, we generated a cHKA-deficient mouse and analyzed its ability to retain K⁺ when fed a control or K⁺-free diet. When maintained on a control diet, homozygous mutant (cHKA(-/-) mice exhibited no deficit in K⁺ homeostasis compared to wild-type (cHKA(+/+) mice. Although fecal K⁺ excretion in cHKA(- /-) mice was double that of cHKA(+/+) mice, fecal K⁺ losses were low compared with urinary K⁺ excretion, which was similar in both groups. When maintained on a K⁺-free diet for 18 d, urinary K⁺ excretion dropped over 100-fold, and to similar levels, in both cHKA(-/-) and cHKA(+/+) mice; fecal K⁺ excretion was reduced in both groups, but losses were fourfold greater in cHKA(-/-) than in cHKA(+/+) mice. Because of the excess loss of K⁺ in the colon, cHKA(-/-) mice exhibited lower plasma and muscle K⁺ than cHKA(+/+) mice. In addition, cHKA(-/-) mice lost twice as much body weight as cHKA(+/+) mice. These results demonstrate that, during K⁺ deprivation, cHKA plays a critical role in the maintenance of K⁺ homeostasis in vivo.