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

Abstract

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

Renal Na+excretion consequent to pharmacogenetic activation of Gq-DREADD in principal cells

“…We also found that MRS2768 decreases ENaC activity in isolated split-open tubules, suggesting one possible cause for this increase in Na ϩ excretion. These findings are in agreement with similar previous observations that 1) ATP and UTP decrease ENaC activity in native principal cells via P2Y 2 receptor-G q signaling (6,25,26,30,33,47); 2) selective P2Y 2 receptor agonism with INS45973 decreases blood pressure, increases Na ϩ excretion, and increases fractional excretion of fluid and Na ϩ in wild-type, but not P2Y 2 receptor knockout, mice; and 3) INS45973 is without effect on GFR in both wild-type and knockout mice (39,40). The effects of both MRS2768 in the present study and INS45973 in this prior study on renal excretion mirror those of the ENaC inhibitor amiloride: they promote a natriuresis without an accompanying change in GFR.…”

Versatility of NaCl transport mechanisms in the cortical collecting duct

“…Mironova et al observed that ENaC activity was not appropriately downregulated in HKA1-null mice on a high-Na + diet, leading to Na + retention and an impaired dipsogenic response. Urinary ATP was lower in HKA1-null mice on a high-Na + diet, relative to WT mice on the same diet, which may explain why ENaC was less inhibited in the KO mice (46).…”

“…conditions (46). Mironova et al observed that ENaC activity was not appropriately downregulated in HKA1-null mice on a high-Na + diet, leading to Na + retention and an impaired dipsogenic response.…”