International Journal of Molecular Sciences

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Open AccessEditorial

The Renin-Angiotensin-Aldosterone System in Metabolic Diseases and Other Pathologies

by Rudy M. Ortiz, Ryousuke Satou, Jia L. Zhuo and Akira Nishiyama

Int. J. Mol. Sci. 2023, 24(8), 7413; https://doi.org/10.3390/ijms24087413 - 18 Apr 2023

Cited by 1 | Viewed by 1242

Abstract

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: (1) Renin-Angiotensin-Aldosterone System in Pathologies and (2) Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...] Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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14 pages, 1775 KiB

Open AccessArticle

Glucose Increases Hepatic Mitochondrial Antioxidant Enzyme Activities in Insulin Resistant Rats Following Chronic Angiotensin Receptor Blockade

by Jose A. Godoy-Lugo, Max A. Thorwald, Dora A. Mendez, Ruben Rodriguez, Daisuke Nakano, Akira Nishiyama and Rudy M. Ortiz

Int. J. Mol. Sci. 2022, 23(18), 10897; https://doi.org/10.3390/ijms231810897 - 17 Sep 2022

Cited by 3 | Viewed by 2238

Abstract

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world’s population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world’s population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1β) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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13 pages, 4626 KiB

Open AccessArticle

Association of Antihypertensive Effects of Esaxerenone with the Internal Sodium Balance in Dahl Salt-Sensitive Hypertensive Rats

by Mai Hattori, Asadur Rahman, Satoshi Kidoguchi, Nourin Jahan, Yoshihide Fujisawa, Norihiko Morisawa, Hiroyuki Ohsaki, Hideki Kobara, Tsutomu Masaki, Akram Hossain, Akumwami Steeve and Akira Nishiyama

Int. J. Mol. Sci. 2022, 23(16), 8915; https://doi.org/10.3390/ijms23168915 - 10 Aug 2022

Cited by 1 | Viewed by 2092

Abstract

Background: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). Objective: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. Methods: In the different experimental setups, we [...] Read more.

Background: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). Objective: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. Methods: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. Results: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. Conclusions: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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13 pages, 2473 KiB

Open AccessArticle

Immunosuppression by Mycophenolate Mofetil Mitigates Intrarenal Angiotensinogen Augmentation in Angiotensin II-Dependent Hypertension

by Ryousuke Satou, Martha Franco, Courtney M. Dugas, Akemi Katsurada and L. Gabriel Navar

Int. J. Mol. Sci. 2022, 23(14), 7680; https://doi.org/10.3390/ijms23147680 - 12 Jul 2022

Cited by 6 | Viewed by 1933

Abstract

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in [...] Read more.

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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Review

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16 pages, 2930 KiB

Open AccessReview

Angiotensin II and AT_1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension

by Ana Paula de Oliveira Leite, Xiao C. Li, Sarah M. Nwia, Rumana Hassan and Jia L. Zhuo

Int. J. Mol. Sci. 2022, 23(5), 2402; https://doi.org/10.3390/ijms23052402 - 22 Feb 2022

Cited by 7 | Viewed by 3794

Abstract

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development [...] Read more.

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT₁ (AT_1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT₁ (AT_1a) receptors or its direct downstream target Na⁺/H⁺ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT₁ (AT_1a) receptors selectively in the proximal tubules increases proximal tubule Na⁺ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT₁ (AT_1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT₁ (AT_1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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11 pages, 822 KiB

Open AccessReview

Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule

by Robert M. Carey, Helmy M. Siragy, John J. Gildea and Susanna R. Keller

Int. J. Mol. Sci. 2022, 23(4), 2317; https://doi.org/10.3390/ijms23042317 - 19 Feb 2022

Cited by 9 | Viewed by 2544

Abstract

Angiotensin II (Ang II) type-2 receptors (AT₂R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na⁺) retention induced by Ang II stimulation of Ang II [...] Read more.

Angiotensin II (Ang II) type-2 receptors (AT₂R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na⁺) retention induced by Ang II stimulation of Ang II type-1 receptor (AT₁R). Natriuresis induced by AT₁R blockade is due at least in part to AT₂R activation and whole body deletion of AT₂Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT₂R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na⁺ reabsorption by the AT₂R is the renal proximal tubule (RPT). AT₂Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT₂R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT₂Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT₂R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT₂R agonists are candidates for proximal tubule natriuretic agents in Na⁺ and fluid retention disorders. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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33 pages, 1543 KiB

Open AccessReview

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

by Tomas Rajtik, Peter Galis, Linda Bartosova, Ludovit Paulis, Eva Goncalvesova and Jan Klimas

Int. J. Mol. Sci. 2021, 22(23), 12800; https://doi.org/10.3390/ijms222312800 - 26 Nov 2021

Cited by 10 | Viewed by 3480

Abstract

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor [...] Read more.

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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16 pages, 1433 KiB

Open AccessReview

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension

by Julia Shanks and Rohit Ramchandra

Int. J. Mol. Sci. 2021, 22(22), 12305; https://doi.org/10.3390/ijms222212305 - 14 Nov 2021

Cited by 27 | Viewed by 8995

Abstract

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the [...] Read more.

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed. Full article

(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System in Pathologies)

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