Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease.

biomolecules Review Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease Stefania Gorini 1 , Vincenzo Marzolla 1 , Caterina Mammi 1 , Andrea Armani 1 and Massimiliano Caprio 1,2, * 1 2 * Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy; (S.G.); (V.M.); (C.M.); (A.A.) Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy Correspondence: ; Tel.: +39-06-5225-3419; Fax: +39-06-5225-5668 Received: 3 August 2018; Accepted: 12 September 2018; Published: 18 September 2018



 Abstract: The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome. Keywords: mineralocorticoid receptor; aldosterone; PBMC; NGAL; Gal-3; PTGDS; adipose tissue 1. Introduction The mineralocorticoid receptor (MR) is a member of the nuclear receptor family and acts as a ligand-dependent transcription factor. It was initially identified to regulate blood pressure through its ability to modulate renal sodium handling in response to aldosterone [1–3]. Importantly, aldosterone is not the exclusive ligand of MR. Cortisol and aldosterone display similar affinity and specificity for the MR [4]. In tissues with low 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity, which converts cortisol to inactive cortisone, MR activation is mainly regulated by circulating glucocorticoids [5]. It is now evident that the MR is expressed in many tissues other than the kidney. Importantly, MR is expressed in the heart [6,7], in all cell types of the vasculature, including smooth muscle cells (SMCs), endothelial cells (ECs) and fibroblasts, and has also been found in adipose tissue [8]. In this context, the MR has a relevant role in the control of cardiovascular and metabolic function [9–11]. Biomolecules 2018, 8, 96; doi:10.3390/biom8030096 www.mdpi.com/journal/biomolecules Biomolecules 2018, 8, 96 2 of 20 Dysregulation of the aldosterone/MR signaling has been identified as an important cause of several diseases. Indeed, high plasma levels of aldosterone are strictly associated with hypertension, obesity and increased cardiovascular risk [12]. Several studies demonstrated that obese and hypertensive patients display increased plasma and urinary levels of aldosterone [13–15]. Molecular mechanisms underlying vascular changes in hypertension are not completely understood, but a role for aldosterone has been suggested. Accumulating evidence has demonstrated that aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling [16,17]. Indeed, MR activation in human coronary artery SMCs regulates several genes involved in vascular fibrosis, calcification and inflammation, such as collagen types I and III, the parathyroid hormone receptors and interleukin (IL)-16 [16]. The MR is known to regulate genes involved in inflammation and oxidative stress in human coronary ECs [10]. Reactive oxygen species (ROS) have also been suggested to mediate the detrimental effects of aldosterone in the vasculature through MR activation [18,19]. Ligand-independent transcriptional activation of the MR has also been described, since MR can be activated under conditions of high oxidative stress, even without any increase in circulating agonists [20]. It is now clear that several molecules, other than aldosterone, can activate MR. For instance, Rac1 represents an important activator of MR. It is a small GTPase belonging to the Rho family and it is involved in the activation of MR in the kidney and in the heart [21–23]. Rac1 overexpression in cardiomyocytes of rats upregulates MR transcription [24]. Its overexpression in a mouse model of pressure overload-induced heart failure (HF) can increase MR protein and MR target genes expression in the heart [23]. Clinical evidence suggests that the interaction between Rac1 and MR plays a major role in cardiovascular damage induced by high sodium intake in humans as Rac1 expression positively correlates with MR expression under high sodium intake dietary regimens [25]. In addition to its classical genomic effects, aldosterone elicits rapid actions that do not require transcription or translation. These effects can be mediated by crosstalk of the MR with several membrane-associated signaling pathways, including transactivation of tyrosine kinases (i.e., epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and insulin-like-growth factor 1 receptor (IGF1R) [26], or G protein coupled receptors. Among these, G protein-coupled estrogen receptor 1 (GPER1) has been proposed as a novel aldosterone receptor, even if a direct binding or interaction between GPER1 and aldosterone still awaits demonstration [27]. Such immediate effects are mostly involved in ion transport, but play also a relevant role in extrarenal tissues, contributing to the pathophysiological effects of MR and leading to inflammation, fibrosis and organ damage. Notably, genomic and nongenomic MR signaling interact closely, and their combined effect determines the long-term impact of altered MR activation at the level of vessels, heart and kidney [28–30]. This aspect was extensively reviewed by Ruhs et al. [26]. This review discusses the global pathophysiological relevance of aldosterone and MR-related pathways in cardiometabolic disease and obesity. In this context, we discuss the role of potential novel biomarkers related to the ald (...truncated)