ENaC activity in the cortical collecting duct of HKα1 H+,K+-ATPase knockout mice is uncoupled from Na+ intake

Modulation of the epithelial Na + channel (ENaC) activity in the collecting duct (CD) is an important mechanism for normal Na + homeostasis. ENaC activity is inversely related to dietary Na + intake, in part due to inhibitory paracrine purinergic regulation. Evidence suggests that H + ,K + -ATPase activity in the CD also influences Na + excretion. We hypothesized that renal H + ,K + -ATPases affect Na + reabsorption by the CD by modulating ENaC activity. ENaC activity in HKα 1 H + ,K + -ATPase knockout (HKα 1 −/− ) mice was uncoupled from Na + intake. ENaC activity on a high-Na + diet was greater in the HKα 1 −/− mice than in WT mice. Moreover, dietary Na + content did not modulate ENaC activity in the HKα 1 −/− mice as it did in WT mice. Purinergic regulation of ENaC was abnormal in HKα 1 −/− mice. In contrast to WT mice, where urinary [ATP] was proportional to dietary Na + intake, urinary [ATP] did not increase in response to a high-Na + diet in the HKα 1 −/− mice and was significantly lower than in the WT mice. HKα 1 −/− mice fed a high-Na + diet had greater Na + retention than WT mice and had an impaired dipsogenic response. These results suggest an important role for the HKα 1 subunit in the regulation of purinergic signaling in the CD. They are also consistent with HKα 1 -containing H + ,K + -ATPases as important components for the proper regulation of Na + balance and the dipsogenic response to a high-salt diet. Such observations suggest a previously unrecognized element in Na + regulation in the CD.