Editorial related to the special issue: “Extrarenal functions of the renin-angiotensin-system”

A recent collection of five review articles published in this journal highlights some state-of-the-art research that has been presented at the Gordon Research Conference on Angiotensin in February 2024. These articles feature a broad spectrum of research areas related to the renin-angiotensin-aldosterone system (RAAS), authored by experts in the field.

Two articles of this collection focus on novel approaches for the understanding of angiotensin receptor signaling.^{1, 2} Gironacci and Bruna-Haupt elucidate how RAAS receptor dimerization with other RAAS- or non-RAAS receptors alters receptor affinity, trafficking, signaling, and biological function.^{1, 3} For example, cross-inhibition is a dimer-specific phenomenon leading to antagonism of one receptor in a dimer by an antagonist specific for the other receptor in the dimer. New drug candidates are in development that target receptor dimers instead of single receptors, making use of dimer-specific crosstalk between receptors. However, the authors also point out that receptor dimerization and its functional consequences are understudied, which means that many drug actions caused by receptor dimerization (e.g. AT₁-receptor antagonism by beta₂-adrenergic receptor antagonists⁴) are underestimated and their potential clinical consequences unknown and not taken into therapeutic consideration.¹

Verano-Braga, Steckelings, and co-authors highlight new approaches to study angiotensin receptor signaling through quantitative phosphoproteomics, i.e. the monitoring of all protein phospho- and dephosphorylation events in a cell, as a hypothesis-generating method for identifying so-far unknown angiotensin receptor signaling mechanisms.² The article reviews the literature on phosphoproteomics addressing biased signaling, beta-arrestin-dependent AT₁-receptor (AT₁R) signaling, or signaling of receptors of the protective arm of the RAAS, namely AT₂-receptor (AT₂R), receptor Mas, and Mas-related G-protein coupled receptor D (MrGD). While all angiotensin receptors are categorized as being G-protein coupled receptors (GPCRs), receptors of the protective arm of the RAAS usually do not induce “classical” GPCR-mediated signaling cascades but rather unconventional, and in large part unknown, pathways, which makes a non-targeted methodology for their identification a useful approach. Extrarenal effects of the protective arm of the RAAS identified by phosphoproteomics include anti-senescence effects (e.g. inhibition of mTOR signaling), effects on histone acetylation with impact on cell cycle control and tumor-suppressor (p53) actions, or effects on glucose homeostasis.^5-8

The article highlights future applications of this technology, such as the exploration of cell-specific angiotensin receptor signaling or signaling of RAAS receptor dimers.²

The group of Marques focuses on the role of the gut microbiome and the gut–immune axis in cardiovascular disease.⁹ The article describes the complex cross-talk and delicate equilibrium between diet, gut microbiota, composition of resident inflammatory cells, systemic low-grade inflammation, and cardiovascular disease (CVD).⁹ It further elucidates the concept of the microbiota–gut–brain axis, which comprises “top-down” and “bottom-up” signaling mechanisms. For example, ischemic stroke elicits “top-down” signaling to the gut—likely involving vagal nerves—resulting in dysbiosis and dysmotility and subsequently systemic inflammation, which may be causative of complications (such as pneumonia) and a worse prognosis in patients. “Bottom-up” signaling seems essential for central immune system maturation, and certain microbiota-derived fiber metabolites [short-chain fatty acids (SCFAs)] have been shown to play a protective role in stroke and other CVD by anti-hypertensive and anti-inflammatory effects.¹⁰

Although this review article does not focus on the interplay between the RAAS and the microbiome in the context of CVD, such studies have been performed by the Marques group and others and—for example—revealed that angiotensin II (Ang II) reduces α- and β- microbiota diversity, including Clostridium leptum, which is responsible for the generation of the protective SCFA metabolite.^11-13 Furthermore, Ang II effects on microbiota may aggravate Ang II-induced vascular inflammation and dysfunction.^11-13

The review contributed by the Touyz group features another important player for cardiovascular homeostasis, namely transient receptor potential melastatin 7 (TRPM7) cation channels.¹⁴ TRPM7 channel activity can be significantly modified by the RAAS, making this channel an often-overlooked contributor to the many orchestrated RAAS effects that eventually lead to changes in CV physiology and disease.^{14, 15} TRPM7 channels play an essential role in the control of intracellular Mg²⁺, which is an essential co-factor in many enzymatic reactions and is critically involved in ATPase-dependent processes. Mg²⁺ influences over 600 enzymes, thus having a significant impact on cell metabolism. The review article provides an in-depth review of the role of TRPM7 channels in vascular endothelial and vascular smooth muscle cells.¹⁴ For example, the authors point out that normal TRPM7 channel function in endothelial cells is essential for nitric oxide synthesis, glucose metabolism (and a potential link between the two), a balanced redox status, as well as prevention of cell senescence and endothelial dysfunction. In vascular smooth muscle cells, TRPM7 channels contribute to cell proliferation, contraction, phenotypic switching, remodeling, and calcification—all of this being cellular effects in which TRPM7 channels are also involved in Ang II and aldosterone actions.

The review article by Kalupahana and Moustaid-Moussa introduces the importance of extra-renal, non-cardiovascular effects. This is a relatively new area of research in the field where the RAAS influences metabolic disease (e.g. glucose/lipid metabolism or obesity) and cancer (in particular breast cancer).¹⁶ Activation of RAAS receptors has been reported to either promote (AT₁R) or inhibit (AT₂R) insulin resistance and dyslipidaemia,¹⁷ or cancer cell growth.^{5, 6, 18} The article first reviews RAAS effects on metabolism or cancer separately and then develops a unified view and hypothesis, which is that angiotensin II promotes metabolic changes within tumor cells, particularly de novo fatty acid synthesis, which contributes to the growth and survival of these cells. They further suggest that adipocyte-derived factors can promote tumor growth in tissues rich in white-adipose fat (e.g. breast tissue) and that the development of a pro-tumorigenic milieu in adipocytes is—at least partly—RAAS dependent since the treatment of adipocytes with ACE-inhibitors or AT₁R antagonists attenuates the pro-tumorigenic effect.¹⁹ Consequently, the authors discuss RAAS inhibition as a therapeutic approach in cancer patients and suggest RAAS inhibition as potential neoadjuvant therapy based on improved outcomes under RAAS blockade in clinical trials in patients with hepatocellular carcinoma, renal cell carcinoma, colorectal cancer, and pancreatic cancer.²⁰ They also see potential in the treatment of breast cancer with confirmed AT₁R expression. However, more clinical trials, in particular sufficiently powered, randomly controlled, prospective studies, are warranted to decide whether RAAS-targeting drugs should be used in cancer patients and under which specific conditions.

As diverse as the topics of these articles are, they support one important conclusion, which is that since the discovery of the RAAS as a sodium/water-retaining, blood pressure (BP) rising hormonal system between 1897 and the mid of the last century, research has not only grown and refined our knowledge on the mechanisms by which the RAAS regulates BP and sodium homeostasis, but also expanded into areas of RAAS actions that are completely distinct from renal or cardiovascular effects (Figure 1). Nevertheless, awareness of these non-renal/−cardiovascular effects is still rather low, which likely has three main reasons: (1) initially and for decades, RAAS research exclusively comprised studies about renal/cardiovascular actions, (2) knowledge transfer on the RAAS in teaching and textbooks is still widely limited to cardiovascular/renal effects, and (3) clinically approved drugs targeting the RAAS are exclusively (and very frequently) used for cardiovascular and renal disease (e.g. treatment of hypertension, heart failure, chronic/diabetic kidney disease). Therefore, the perception of the RAAS has in large part been dictated by the context of its first discovery. Had this context been different—for example, as a hormone that modifies glucose metabolism—who knows how the RAAS would be considered today.

New RAAS-targeting drugs in development, especially those targeting the protective arm of the RAAS, will likely change and widen our view of the RAAS. For example, the furthest advanced drug targeting the protective RAAS, the AT₂R agonist buloxibutid (previously C21), is currently in a Phase IIb clinical trial with FDA fast track designation for idiopathic pulmonary fibrosis (ClinicalTrials.gov ID NCT06588686), a disease that is completely unrelated to the cardiovascular/renal RAAS.