**1. Introduction**

Hypertension is not only one of the most frequent diseases in the world, but it is also a key risk factor for cardiovascular disease and renal dysfunction. The kidney plays a pivotal role in the regulation of body fluid levels and blood pressure (BP), and an impaired kidney function comprises a major mechanism that alters the salt sensitivity of BP [1]. Because renal salt handling is critical for maintaining an independent life for terrestrial mammals, these animals have developed highly differentiated diverse tubule cells that are involved in the transport of sodium and other ions. The major renal sodium transporters and channels include Na+/H<sup>+</sup> exchanger isoform 3 (NHE3) in the proximal tubule (PT), Na<sup>+</sup>-K<sup>+</sup>-2Cl− cotransporter (NKCC2) in the thick ascending limb (TAL), Na<sup>+</sup>-Cl− cotransporter (NCC) in the distal convoluted tubule (DCT), and epithelial sodium channel (ENaC) and Cl−/HCO3− exchanger pendrin in the connecting tubule (CNT) and the collecting duct (CD). The significance of several of these transporters and their regulators in the renal nephron has been confirmed by the monogenic hypertensive or hypotensive disorders [2–4], as well as by the clinical efficacy of the pharmacological agents that block these sodium transport mechanisms.

In addition to the role of the kidney, it is well known that the dysregulation of vascular function significantly contributes to BP elevation [5,6]. The arterial wall consists of intimal endothelial cells, vascular smooth muscle cells, and adventitia. Vascular endothelial cells (VECs) play vital roles in regulating diverse biological functions by secreting various vasoactive factors, including nitric oxide (NO). NO, a strong vasodilator that tightly modulates vascular function, is primarily produced by endothelial NO synthase (eNOS) in endothelial cells [7]. Studies have demonstrated that both genetic and pharmacological ablation of eNOS elicits significant BP elevations [8–10]. Vascular smooth muscle cells (VSMCs) also play important roles in controlling the tonus of blood vessels, thereby regulating BP levels [11].

Ubiquitylation is a stepwise process involving three classes of enzymes. Ubiquitin-activating enzymes (E1s) activate the ubiquitin molecule combined with ATP hydrolysis [12]. Ubiquitin is then transferred to ubiquitin-conjugating enzymes (E2s) with an active cysteine [13,14]. Following this, ubiquitin is transferred to substrates via the ubiquitin protein ligases (E3s). Humans have only one E1, ~40 E2s, and 500–1000 of E3s [15–17]. Two types of E3s exist, termed the homologous to the E6-AP C terminus and the really interesting new gene (RING). E3s provide substrate specificity to the ubiquitin system and recognize multiple substrates through di fferent protein–protein interactions, thus regulating multiple cellular processes, including DNA damage repair, cell cycle progression, development, and signal transduction. Given that the ubiquitin proteasome system (UPS) enables adaptation to physiological challenges by controlling the protein abundance of target substrates, the involvement of UPS in BP regulation has attracted extensive research attention. In this article, we review the role of UPS in BP homeostasis, especially focusing on sodium transporters of the kidney and vascular functions (Figure 1).

**Figure 1.** The role of ubiquitin proteasome system in fluid volume and blood pressure regulation. PT, proximal tubule; TAL, thick ascending limb; DCT, distal convoluted tubule; CNT, connecting tubule; CD, collecting duct.

### **2. Role of UPS in the Regulation of Tubular Function in the Kidney**
