Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Abstract

The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT 1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT 2R) and ANG-(1-7) (AT 7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT 7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT 2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. renin-angiotensin system; angiotensin converting enzyme; ACE2; neprilysin; kidney; nuclei; AT 1 ; AT 2 ; AT 7 , FROM THE EARLY STUDIES OF Tigerstedt and Bergman (101) that described renin activity in the kidney to the characterization of a pressor substance subsequently identified as ANG II by the laboratories of Braun-Menendez (6) (hypertensin) and Page (angiotonin) 50 years later (8), the characterization of the renin-angiotensin system (RAS) within the kidney and other tissues continues unabated to broaden our understanding of the functional aspects of this important hormonal system in blood pressure regulation and cardiovascular pathologies. Coupled with the discoveries of ANG I-converting enzyme (ACE) as the primary enzyme that forms ANG II in the circulation and tissue and the molecular identification of the ANG II type 1 receptor (AT 1 ) that confers the predominant actions of ANG II, the "classical" RAS was regarded as a sequential endocrine system to form ANG II for the maintenance of blood pressure through renal, vascular, and central mechanisms. There is, however, overwhelming evidence for a "nonclassical" RAS that results in the formation of novel peptide products with functional properties distinct from that of the ANG II-AT 1 receptor pathway (5,12,14,67,8...

Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT1a/MAPK/NF-кB signaling pathways

“…10). This explanation is further supported by the reports that AT 1 (AT 1a ) receptors are localized in the endosomal (15,61), mitochondrial (1), and nuclear compartments (13,33,38,47). However, it should be pointed out that, not confined to AGT expression, the AT 1a / MAP kinase signaling pathways also mediate the effects of ECFP/ANG II on transcriptional responses of transforming growth factor-␤, MCP-1, and NHE3 expression (28,33).…”

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Intracrine signalling refers to a process whereby a ligand, originating within a target cell or taken up from the extracellular milieu, acts upon an intracellular receptor (reviewed in [9][10][11][62][63][64][65][66][67]). The origin of the ligand for endogenous endothelin receptors remains unknown.…”

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

“…In lieu of earlier studies on intracellular peptide receptors, ANG II and ANG-(1-7) receptors were characterized on isolated nuclei from rat and sheep kidney (54 (Fig. 3, A-C).…”

“…Indeed, the interaction between the circulating RAS components and the cellular or tissue system is likely a dynamic process in vivo that should be examined to a greater extent in cell studies. Finally, the subcellular compartmentalization of angiotensin peptides and other components is becoming increasingly evident (1,2,25,35,40,54,74,140,151). Apart from establishing the functional role of these intracellular systems, a greater emphasis should be placed on the quantification of angiotensins in cellular compartments, and particularly the extent that altered peptide content in tissue reflects discrete changes in the subcellular systems such as the nucleus and mitochondria.…”

“…1). Although originally characterized as a circulating endocrine system that targets both peripheral and central receptors, abundant evidence reveals a tissue-based RAS that influences local cellular actions and exhibits intracellular or subcellular components (2,25,54,71,74,93,134,140,151). The RAS is classically defined by the activity of angiotensin-converting enzyme (ACE) to form angiotensin II (ANG II) and the subsequent activation of the angiotensin type 1 receptor (AT 1 R) to mediate both peripheral and central mechanisms in the regulation of blood pressure.…”