Epithelial Na+ Channel (ENaC), Hormones, and Hypertension

Abstract

This minireview examines both the basic science and clinical observations over the past 20 years to show how and why overstimulation of the amiloride-sensitive epithelial Na ؉ channel (ENaC) expressed by epithelial principal cells of the renal collecting duct may be responsible for a large portion of hypertension in modern society. This idea is based on the finding that, in Liddle syndrome, a mutation of the ␤-and/or ␥-subunits of ENaC produces an activated ion channel, in turn resulting in severe hypertension that is resistant to most forms of conventional antihypertensive therapy. ENaC can also be stimulated to conduct sodium by two hormones: aldosterone and insulin. These hormones are both often elevated in obese individuals with therapy-resistant hypertension. Thus, overstimulation of ENaC by metabolic abnormalities in obese individuals may be a likely cause of the hypertension that accompanies obesity. The molecular mechanisms underlying both Liddle syndrome and obesity-related hypertension are different (i.e. genetic and hormonal, respectively), but both have the same end result, namely increased ENaC activity.

mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

“…Sodium is the major cation in the extracellular fluid, and regulation of its reabsorption and excretion by the kidney plays a primary role in the homeostatic maintenance of fluid volume, body ion composition, and blood pressure (1). Although the majority of Na + reabsorption occurs in the proximal tubule, the distal nephron, particularly the aldosterone-sensitive distal nephron (ASDN), is responsible for fine-tuning of tubule fluid and for determining the net amount of Na + and K + excreted in the urine in response to changes in dietary intake (2).…”

Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

“…It is also well-documented that Sgk1 is subjected to activation by phosphoinositide 3-kinase (Pi3k) and phosphoinositide-dependent kinase 1 (Pdpk1)-mediated signaling cascade, 14,36 as well as by with no lysine kinases Wnk1 and Wnk4. [37][38][39] We did not detect differential expression of genes encoding these protein in the kidney of SHR and hypertensive RIS (Table S2).…”

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

“…In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5).…”

“…epigenetic; chromatin; transcription factor; methylcytosine; methyltransferase; epithelial Na ϩ channel THE EPITHELIAL NA ϩ CHANNEL (ENaC) mediates Na ϩ entry across the apical membranes of salt-absorbing epithelia of the kidney, distal colon, and lung and functions as the rate-limiting step in active transepithelial Na ϩ and fluid absorption. In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5).…”