**1. Introduction**

Arterial hypertension, a major cause of premature death, remains the most prevalent risk factor that is implicated in the development of cardiovascular disease (CVD) and its complications [1]. Globally, the prevalence of hypertension in adults is nearly 32% and 34%, in women and men, respectively [2]. Uncontrolled or untreated high blood pressure (BP) over an extended period of time leads to damage to target organs, including the heart, kidneys, eyes, brain, and arterial blood vessels, causing functional and structural alterations, which could be the clinical manifestations of hypertension-related complications, such as atherosclerosis, heart failure, and chronic kidney disease (CKD) [3]. The dysfunction of vascular smooth muscle cells (VSMCs), among others, that shows the dysregulation in calcium signaling, migrative, and contractile properties is responsible for the mechanism underlying the development of arterial hypertension [3]. Therefore, understanding the molecular players and the modalities and modulation of their function has long been an area of extensive investigation in the field of pathophysiology of hypertension.

Translational research using a variety of animal models that reflect the genetic and environmental factors has significantly contributed to the understanding of the pathophysiologic processes of hypertensive disorders. These efforts have led to the discovery of promising anti-hypertensive drug targets. Among those, Na,K-ATPase, also called the sodium pump, and its repressor, translationally controlled tumor protein (TCTP), have long been the theme of our research using TCTP-overexpressing and TCTP-deficient transgenic mouse models. Cumulative evidence has established that dysregulation of the sodium pump is involved in the development of hypertension and related complications, and that

**Citation:** Maeng, J.; Lee, K. Role of Translationally Controlled Tumor Protein (TCTP) in the Development of Hypertension and Related Diseases in Mouse Models. *Biomedicines* **2022**, *10*, 2722. https://doi.org/10.3390/ biomedicines10112722

Academic Editors: Josef Zicha and Ivana Vanˇeˇcková

Received: 13 September 2022 Accepted: 24 October 2022 Published: 27 October 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

inhibitors of Na,K-ATPase can induce the hypertensive status. Prolonged suppression of Na,K-ATPase by ouabain, a well-established extracellular inhibitor of the sodium pump, has been shown to result in the development of hypertension in vivo [4–6]. Analogous to the action of ouabain, transgenic overexpression of TCTP, an intracellular inhibitor of Na,K-ATPase, showed phenotypes of systemic arterial hypertension in vivo, suggesting the causative role of TCTP as an inhibitor of Na,K-ATPase.

This review attempts to describe the current status of our understanding of the role of TCTP in hypertensive disorders and related diseases, such as atherosclerosis and cataracts, as a consequence of its ability to suppress Na,K-ATPase, and to collate what we have learned from the studies using genetically engineered animal models. Therefore, studies that examined the role of TCTP in the pathophysiology of arterial hypertension and potentially related conditions such as atherosclerosis, heart failure, and obesity, if any, were included for the description in the present review. In addition, studies that use genetically engineered mouse models whose TCTP expression was overexpressed or reduced either systemically or tissue-specifically, were included, whereas research that dealt with non-genetic models or genetic models unrelated to TCTP were excluded in this study.

#### **2. Pathophysiological Consequences of Na,K-ATPase Inhibition**

Na,K-ATPase is an essential cell surface enzyme, which maintains ion gradients between the intracellular space and extracellular fluids [7]. This pump consists of three distinctive subunits, which appear in several isoforms. These isoforms include four α isoform (α1~4) and three β isoform (β1~3) subunits and an optional third γ subunit, a member of a Phe-X-Tyr-Asp (FXYD) motif-containing FXYD family [8]. The catalytic α and β subunits are required for ion-pumping activity while the β subunit affects the activity of this pump. Members of the FXYD proteins regulate the Na,K-ATPase activity in specific tissues [8]. The catalytic α subunit that consists of three cytoplasmic domains and ten transmembrane (TM) domains offers the binding sites for Na+, K+, and ATP as well as for cardiotonic steroids (CTSs), such as ouabain [9]. The high degree of conservation of the ouabain-binding site of this enzyme implies the existence of potential endogenous regulators [8].

Several endogenous "digitalis-like" or "ouabain-like" factors have been identified as a circulatory moiety that inhibits Na,K-ATPase [7]. The identification of endogenous CTS-like activity and the observation that Na,K-ATPase subunits exist in several isoforms imply the hormone-like functions of CTS and receptor-like function of the sodium pump [10]. Numerous investigations have found that CTS in relation with the sodium pump mediates various signaling cascades related to cell growth and division, release of endothelin-1 (ET-1) by endothelial cells, and other effects in cells [10]. Thus far, two distinctive, but coupled, pathways have been identified in the cellular signaling of Na,K-ATPase not only as an ion pump but also as a signaling transducer [10–13]. Therefore, dysregulation of this pump in both pathways has been an area of attention due to its pathophysiologic association with hypertension and the complications thereof [9].
