Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

Abstract

The renin-angiotensin-aldosterone system (RAAS) has been identified as the main system involved in blood pressure regulation, renal hemodynamics, and sodium-volume homeostasis. Furthermore, the RAAS directly affects vascular and cardiac remodeling through proliferative and inflammatory signaling. Pharmacological targeting of the RAAS is a consolidated and evidence-based approach in the treatment of various aspects of cardiovascular disease. An exploding number of recent studies have provided novel insights into nuclear receptor biology in relation to cardiovascular (patho)physiology. In particular, members of the nuclear hormone receptor (NHR) superfamily have been identified as key molecules in various relevant cellular processes. As such, NHRs have been proposed as amenable targets for therapy, and their role in cardiovascular disease is currently explored. This review focuses on the potential effects of NHRs on the RAAS, summarizing the extensive body of evidence from experimental, animal, and clinical studies, suggesting that NHRs and the RAAS are closely intertwined. We discuss how these findings might translate into the clinical setting and discuss the (older) trials that evaluated NHR agonists in humans. We postulate that therapies targeting NHRs will cause ancillary effects (ie, modulating the RAAS) that need to be considered. NHRs constitute a superfamily of ligand-activated transcription factors involved in multiple cellular functions, acting as monomers, homodimers, or heterodimers (usually with the retinoid X receptors). The NHR superfamily is divided into 6 subfamilies (Table S1, available in the data supplement online at http://hyper.ahajournals.org).1 Cloning of the NHRs revealed that many of the NHRs share close homology. The fourth, fifth, and sixth classes (not mentioned in Table S1) include various NHRs that are less well described. NHR ligands include hormones, xenobiotics, prostaglandins, fatty acids, and cholesterol derivatives. An overwhelming amount of evidence exists for the role of NHR in cholesterol, lipid, and glucose metabolism.2 Several NHRs are provisionally indicated as …