Regulation of the epithelial sodium channel [ENaC] in kidneys of salt-sensitive Dahl rats: Insights on alternative splicing

Abstract

The epithelial sodium channel [ENaC] is critical for the maintenance of sodium balance, extracellular fluid volume and long term blood pressure control. Monogenic disorders causing ENaC hyperactivity have led to a severe form of hereditary hypertension in humans, known as Liddle's syndrome. Similarly, in animal models, ENaC hyperactivity has been well documented in kidneys of salt-sensitive [S] Dahl rats [a genetic model of salt-sensitive hypertension] versus their normotensive control [Dahl salt-resistant [R] rats]. The purpose of the present review is to highlight the differential regulation of ENaC in kidneys of Dahl S versus R rats. A systematic overview of the putative role of alternative splicing of the main α subunit of ENaC [α ENaC] in modulating ENaC expression in kidneys of Dahl rats will be discussed. Finally, a better understanding of the meaningful contribution of ENaC in the pathogenesis of salt-sensitive hypertension will be achieved upon completion of this review. Salt-sensitive hypertensionOver one-fifth of Canadian adults are diagnosed with hypertension http://www.statcan.com and over 50% of primary hypertensive patients are salt-sensitive [1]. Despite the fact that hypertension is the primary risk factor for stroke and heart disease, and has been labeled by the "silent killer disease", yet 42% of Canadians are still unaware of their increased blood pressures http:// www.heartandstroke.com/site/c.ikIQLcMWJtE/ b.3484023/.These above statistics, combined with the realization that salt-sensitive hypertension exacerbates mortality rates [2], worsens manifestations of target organ damage [3,4] and is a common finding in aging populations, emphasize the importance of identifying novel targets for prevention and treatment of salt-sensitive hypertension.The major contributor to the pathogenesis of salt-sensitive hypertension is dietary salt [5]. Dietary sodium, in turn, has sodium chloride [NaCl] as its major constituent. The sodium ion [Na + ] is transported into the superficial cells of several organs (see below) primarily via the amiloridesensitive Epithelial Sodium Channel [ENaC]. Owing to the fact that inadequate Na + excretion is a risk factor for hypertension, ENaC represents an attractive therapeutic target to study in salt-sensitive hypertension and α ENaC regulation by alternative splicing will be the focus of the present review.

Transient Receptor Potential Vanilloid 1 Activation by Dietary Capsaicin Promotes Urinary Sodium Excretion by Inhibiting Epithelial Sodium Channel α Subunit–Mediated Sodium Reabsorption

“…High-salt intake affects renal ENaC activity, and the ENaC expression level may constitute the critical role of ENaC in salt-sensitive hypertension. 19 However, how to restore ENaC dysfunction with high-salt intakes remains an obstacle. For patients with hypertension, thiazide and loop diuretics and amiloride are used to promote the U Na V by inhibiting sodium/chloride reabsorption, which involves in NCC, Na/K/2Cl cotransporter, and ENaC.…”

ENaCs and ASICs as therapeutic targets

“…Serum-glucocorticoid kinase 1 (SGK1), which regulates multiple effector proteins including ENaC (95,124,237,302), regulates transcription of ␣ENaC by phosphorylating Af9, preventing the Af9/Dot1a interaction and consequently increasing ␣ENaC expression (439); Dot1a, in turn, downregulates expression of SGK1 (320,435), and downregulates 11-␤-hydroxysteroid dehydrogenase thereby increasing the responsiveness of tissues expressing the mineralocorticoid receptor to glucocorticoids (276). There may also be a role for ␣ENaC splice variants in the expression of the full-length ENaC subunits, as increased transcription and translation of shortened splice variants may underlie the rescue of Dahl salt-resistant rats from the deleterious consequences of a high-salt diet by interfering with normal channel assembly (344,345). Interestingly, expression of ENaC subunits is greater in Dahl salt-sensitive rats than in the Dahl salt-resistant rats, and is further increased when these animals are placed on a high-salt diet (9,11).…”

Investigation on Genetic Heterogeneity of α-Subunit of the Epithelial Sodium Channel in Rat Renal Cortex

“…This attention can be explained by specifi c features of nucleotide sequences of DNA encoding sodium channel subunits. Deletions and untranslated sequences determine the existence of several mRNA forms for each subunit isoform, which modulates the properties of sodium channel [7,8]. Such diversity was not observed in cell cultures, because standard cDNA containing no untranslated sequences or deletions characteristic of native DNA are used for evaluation of the expression of ENaC subunits [9].…”

“…ENaC consists of α-, β-, and γ-subunits (2:1:1 ratio) surrounding the channel pore conducting sodium ions [3]. The causes of species-and tissue-specifi c variability of sodium channel properties attract much recent attention [5,7]. This attention can be explained by specifi c features of nucleotide sequences of DNA encoding sodium channel subunits.…”

“…ENaC α-subunit contributes most to the heterogeneity of the channel properties. It is known that N-terminal of human αENaC contains a large untranslated DNA sequence determining a reading frame shift and production of sodium channel molecules of different activity [2,[7][8][9]. On the other hand, deletion detected at the 3'-fl anking region of the α-subunit DNA leads to alternative splicing [4] and their appearance of deletional α-subunit mRNA (a and b) forms of the epithelial sodium channel (αENaC) in addition to its wild type.…”