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 HKα₁ H⁺,K⁺-ATPase knockout (HKα₁^-/-) mice was uncoupled from Na⁺ intake. ENaC activity on a high-Na⁺ diet was greater in the HKα₁^-/- mice than in WT mice. Moreover, dietary Na⁺ content did not modulate ENaC activity in the HKα₁^-/- mice as it did in WT mice. Purinergic regulation of ENaC was abnormal in HKα₁^-/- 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 HKα₁^-/- mice and was significantly lower than in the WT mice. HKα₁^-/- 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 HKα₁ subunit in the regulation of purinergic signaling in the CD. They are also consistent with HKα₁-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.

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