Epithelial sodium channels and its role in blood pressure regulation.
...r two subunits is less certain. Neither the b- nor g- subunit, when expressed alone or together, produced any measurable Na+ current. However, coexpression with the a-subunit greatly enhanced the amplitudes of the Na+ current (Canessa et al, 1994; Schild et al, 1995). These results indicate that the b- and g- subunits probably have a structural and/or regulatory role in the stabilization and function of the channel. The activity of amiloride-sensitive sodium channels is regulated by aldosterone and vasopressin, hormones that modulate sodium balance and thus control blood volume and blood pressure (Kemendy et al, 1992; Schafer and Hawk, 1992; Pacha et al, 1993). What regulates ENaCs? The activity of the sodium channel responds to a wide variety of hormones and changes in physiological conditions. Channel activity can be modulated by several hormones and in particular aldosterone, antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP) (Rossier, B.C., Pradervand, S et al. 1992). Aldosterone: Aldosterone is a hormone released by the adrenal glands. It is part of the complex mechanism used by the body to regulate blood pressure. It increases the reabsorption of sodium and water along with the excretion of potassium in the distal tubules of the kidneys. This action raises blood pressure. Aldosterone also stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which acts upon the kidneys to increase fluid retention. THE ROLE OF ENaC IN THE REGULATION OF BLOOD PRESSURE Among many factors affecting the blood pressure variation, the kidney plays an important role in the long-term regulation of sodium balance, blood volume, and blood pressure via pressure diuresis and pressure natriuresis (Guyton et al, 1972a; Liard et al, 1974). The kidney regulates extracellular fluid volume by tightly controlling sodium balance. The total amount of exchangeable sodium therefore determines both the extracellular fluid volume and blood pressure. Thus, although many systems can influence blood pressure in the short term, the long-term blood pressure setting ultimately depends on renal sodium handling (Guyton et al, 1972b). The sodium transporters (i.e ENaC) in the kidney are responsible for sodium reabsorption and fluid balance and are therefore important candidates for involvement in the development of hypertension. Polymorphisms of ENaC that inactivates the channels cause low blood pressure (e.g pseudohypoaldosteronism) whereas polymorphisms of ENaC that activate the channels cause high blood pressure as observed in Liddle’s syndrome. These single gene disorders demonstrate the central role that ENaC plays in blood pressure homeostasis. Gain of function mutations: Liddle's syndrome, an autosomal dominant hereditary form of hypertension, is characterized by an early and severe hypertension, often accompanied by metabolic alkalosis and hypokalemia (Liddle et al 1963.), all signs that are characteristic of an excess of aldosterone (Conn's syndrome). The plasma level of aldosterone is however low. For this reason, Liddle's syndrome is also called pseudoaldosteronism. This severe form of hypertension is remarkably responsive to treatment with a low-salt diet and Na+ channel inhibitors (K+-sparing diuretics), suggesting a primary defective regulation of the ENaC. Indeed, linkage studies showed that this trait was due to mutations in the genes of ENaC subunits (Shimkets et al 1994). These mutations are all localized in the COOH-terminal region of the -subunit and -subunit (Hansson et al 1995). Furthermore, these mutations all modify the so-called "PY" motif (the consensus sequence PPXY) either by missense mutations, by introduction of an upstream frameshift, or by a stop codon that results in elimination of the PY motif. In expression systems, these mutations have been shown to result in the overexpression of Na+ channels that are hyperactive compared with the wild-type ENaC (Schild, L et al 1995). More precisely, Kellenberger et al. have shown that these mutations prevent the downregulation of the channel that normally occurs with a rise in intracellular Na+: ENaC channels bearing the Liddle's mutation remain in a highly active state despite a high intracellular Na+ concentration. The mechanism of this downregulation is not yet completely elucidated but may involve the binding of the ubiquitin ligase Nedd-4 through a direct interaction of the PY motif in the COOH terminus of ENaC subunits with the WW domain of Nedd-4 (Staub, et al 1996) and/or clathrin-mediated endocytosis (Shimkets, et al 1997). Figure 5 on the next page shows the genetic mutation in Liddle’s syndrome. Figure 5 Mutations causing a reduced ENaC activity: Pseudohypoaldosteronism type 1 (PHA-1) is a heterogenous clinical syndrome characterized by mineralocorticoid end organ resistance, i.e., urinary loss of Na+ and reduced K+ excretion despite an elevated level of aldosterone ( Kuhnle, et al 1997). A severe form of this syndrome is inherited as an autosomal recessive trait, results in sometimes lethal episodes of hyponatremia ("water intoxication."), hypotension, and hyperkalemia, and shows alteration of Na+ transport in several organs, kidney, salivary glands, sweat glands, and colon (Hanukoglu, et al 1991). In several families showing this form of PHA-1, links to mutations in any one of the three ENaC subunits (Chang, et al 1996) were found. A causal link between these mutations and the PHA-1 syndrome was further supported by the demonstration that these mutations resulted in decreased ENaC activity in an artificial expression system (Gründer, et al 1997). A less severe form of PHA-1 with an autosomal dominant mode of inheritance is symptomatic mostly during infancy and improves with age (Kellenberger, et al 1998). ENaC and essential hypertention Polymorphism of ENaC can cause extremes of both high and low blood pressure. This has led investigators to speculate that less fluid variability in ENaC function could account for blood pressure variation in general populations. ENaC abnormalities are particularly likely to underlie high blood pressure in hypertensives with clinical features. Similar to these seen in Liddle’s syndrome such as salt- sensitivity and low plasma rennin activity: low rennin salt-sensitive hypertension is common in people of African descent. Racial difference in the activity of the epithelial sodium channel. Compared with Caucasian, people from African origin appear to retain additional sodium that suppresses secretion of renin and aldosterone. The epithelial sodium channel (ENaC) is an aldosterone-regulated site for sodium reabsorption. ENaC activity could be higher in the African origin person, contributing to sodium retention or, alternatively, lower because of reduced stimulation by aldosterone. To examine the level of ENaC activity in a person of African origin relative to Caucasian, blood p...