**1. Introduction**

Hypertension is a multifactorial disease determined by both genetic and environmental factors, including dietary habit, and is a representative public health issue due to its high prevalence and risk for cardiovascular diseases. The relationship between oral salt intake and elevation of blood pressure were widely observed in clinical trials such as the INTERSALT Study [1], PURE Study [2], and others [3]. The salt sensitivity of blood pressure is defined as "a physiological trait present in rodents and other mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake" [4]. Genetic analyses for hereditary and familial hypertension by positional cloning in the 1990s revealed that ion transporters and their accessory proteins, located in the renal tubules are responsible for the development of genetic hypertension [5]. Based on data from our own [6–14] and other [15–21] studies, we previously reported that important factors in the pathogenesis of salt-sensitive hypertension include the mechanism of sodium reabsorption in the renal tubule and the abnormalities that enhance this reabsorption. Furthermore, we also reported

that angiotensinogen gene single-nucleotide polymorphisms (SNPs) might explain the pathogenesis of this disease at the levels of molecular genetics, human evolution, developmental engineering, and kidney physiology [7–9,11,12,22,23]. Currently, this report describes the already enforced and ongoing investigations into epithelial sodium channels (ENaCs) in terminal nephrons and its regulatory ubiquitinating enzyme, Nedd4L/Nedd4-2, based on our findings, which might provide significant molecular insight into the onset and development of salt-sensitive hypertension.
