*2.2. Regulation of Sodium Reabsorbtion*

It has been speculated that several genes implicated in the regulation of sodium reabsorption in the kidneys were likely selected as an adaptation to high temperature environments, particularly in people from Sub-Saharan Africa [20,57]. These include genes regulating RAAS, such as (Sodium Channel Epithelial 1 Beta Subunit (*SCNN1B*) and Neural Precursor Cell Expressed, Developmentally Down-Regulated 4 (*NEDD4*) that alter sodium retention from the kidneys, and possibly armadillo repeat containing 5 (*ARMC5*) that might be responsible for increased aldosterone production from the adrenal cortex (see below).

These genetic factors may have played an important physiological adaptation ("natural selection") to the low sodium environments and survival of African Americans during their passage from Africa to America on ships [20,57], where they witnessed extreme conditions including severe heat, hyperhidrosis, and fluid loss through sickness. Indeed, this selection process may have contributed to the increased prevalence of hypertension in this population [58,59]. In this section, we cover the most important known genetic contributions to hypertension in African Americans.

## *2.3. ENaC Function*

The amiloride-sensitive epithelial sodium channel (ENaC) is in the distal nephron and responsible for regulating the amount of sodium reabsorbed by the kidneys, primarily through the action of aldosterone. ENaC is composed of 3 homologous subunits of similar structure and encoded by separate genes: Sodium Channel Epithelial 1 Alpha Subunit (*SCNN1A*) on 12p13.31, Sodium Channel Epithelial 1 Beta Subunit (*SCNN1B*) on 16p12.2, and Sodium Channel Epithelial 1 Gamma Subunit (*SCNN1G*) on 16p12.2. There are two transmembrane domains (TM1 and TM2) and two short intracellular domains (*C*- and *N*-terminus); the C-termini contain a binding site for Nedd4 (neural precursor cell expressed, developmentally down-regulated 4), a ubiquitin E3 ligase protein encoded by *NEED4* on 15q21.3 and responsible for the internalization and the proteasomal degradation of ENaC [60–62].

## 2.3.1. Liddle's Syndrome

Constitutive activation variants of *SCNN1B* or *SCNN1G* result in salt-sensitive hypertension known as Liddle's syndrome, an autosomal dominant form of monogenic hypertension that is characterized by early-onset of low-renin hypertension [63]. Patients with Liddle's syndrome are resistant to mineralocorticoid antagonist therapy but respond to an ENaC inhibitor, such as amiloride therapy [63,64]. Gain-of-function variants in the genes encoding for ENaC are in the carboxyterminal cytoplasmic tail of the protein, which is involved in down-regulation of channel number or activity [50,65]. This area of the nephron is the final regulator of sodium balance and activating variants in ENaC leads to sodium retention, potassium excretion, low renin/aldosterone (hyporeninemic hypoaldosteronism), and volume overload [20,66].

## 2.3.2. Hyporeninemic Hypoaldosteronism (Liddle Phenotype)

Hyporeninemic hypoaldosteronism not due to Liddle's syndrome, also referred to as the Liddle phenotype, is more common in African Americans for multiple reasons, including the interplay of certain genes that lead to ethnic differences in proximal and distal tubular sodium reabsorption [67]. Tu et al. confirmed this association between ENaC overreactivity and hypertension in African Americans by demonstrating increased retention of sodium and water after stimulation with 2 weeks of 9-α fludrocortisone [48]. Moreover, ENaC over-activation could also be due to altered internalization and degradation by *NEDD4* and acquired or inherited causes of aldosterone excess. On the other hand, loss-of-function variants in other segments of ENaC cause pseudohypoaldosteronism, an autosomal recessive condition that is characterized by salt-loss and mineralocorticoid resistance [68].
