The interplay between Angiotensin II, TLR4 and hypertension

Miyagishi

Neurogastroenterology Motil

et al. 2020

Background: Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes. Methods:The threshold of visceromotor response (VMR), that is, abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 minutes spectrophotometrically. Key Results: Lipopolysaccharide (1 mg kg −1 ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5-25 mg kg −1 s.c.) for 3 days inhibited these changes in a dose-dependent manner. Moreover, repeated WAS (1 hour daily for 3 days) or intraperitoneal injection of CRF (50 µg kg −1 ) induced the similar visceral changes as LPS, which were also eliminated by losartan. These effects by losartan in LPS model were reversed by GW9662 (a peroxisome proliferator-activated receptor-γ [PPAR-γ] antagonist), N G -nitro-L-arginine methyl ester (a nitric oxide [NO] synthesis inhibitor), or naloxone (an opioid receptor antagonist). Moreover, it also inhibited by sulpiride (a dopamine D 2 receptor antagonist) or domperidone (a peripheral dopamine D 2 antagonist). Conclusion & Inferences:Losartan prevented visceral allodynia and colonic hyperpermeability in rat IBS models. These actions may be PPAR-γ-dependent and also mediated by the NO, opioid, and dopamine D 2 pathways. Losartan may be useful for IBS treatment. K E Y W O R D Sangiotensin II type 1 receptor, gut barrier, irritable bowel syndrome, lipopolysaccharide, visceral sensation

Section: Discussionmentioning

confidence: 76%

Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

Miyagishi

Neurogastroenterology Motil

et al. 2020

“…This activates inflammatory signaling through My88D and activation of nuclear factor-κB, important in cardiac and renal damage and potentially in the development of high BP. 88,89 Moreover, adipokines, such as resistin, may induce hypertension in a TLR4-dependent manner. 90 A recent study in Hypertension demonstrated that TLR4-dependent activation of toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β contribute angiotensin II-induced hypertension and cardiac hypertrophy.…”

Section: Inflammatory Mechanisms Of Hypertension Are Linked To Oxidatmentioning

confidence: 99%

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

2017

Figure.Central role of oxidative stress in accelerated vascular aging in hypertension. AT1R indicates angiotensin II receptor type 1; BH 2 , dihydrobiopterin; BH 4 , tetrahydrobiopterin; BMP, bone morphogenic protein; CypD, cyclophilin D; eNOS, endothelial NO synthase; ET1R, endothelin 1 receptor; H 2 O 2 , hydrogen peroxide; MMP, matrix metalloproteinase; Nox, NADPH oxidase; O 2 −. , superoxide anion; RANTES, regulated on activation, normal T cell expressed and secreted chemokine; and SmgGDS, GTP-binding protein dissociation stimulator. by guest on

“…ROS in turn have many downstream effects that contribute to inflammation, including the activation of several intracellular kinase pathways and the stimulation of redox-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein 1 (AP1; also known as JUN) 30,32,33 . Angiotensin II can also trigger Toll-like receptor 4 (TLR4) activation in various cell types, which stimulates the innate immune response 34 . In addition, angiotensin II has been reported to induce dendritic cell maturation through the NF-κB, extracellular signal-regulated kinase 1 (ERK1)–ERK2 and signal transducer and activator of transcription 1 (STAT1) signalling pathways 35 .…”

Section: Ace In the Immune Systemmentioning

confidence: 99%

Angiotensin-converting enzyme in innate and adaptive immunity

et al. 2018

Angiotensin-converting enzyme (ACE) — a zinc-dependent dicarboxypeptidase with two catalytic domains — plays a major part in blood pressure regulation by converting angiotensin I to angiotensin II. However, ACE cleaves many peptides besides angiotensin I and thereby affects diverse physiological functions, including renal development and male reproduction. In addition, ACE has a role in both innate and adaptive responses by modulating macrophage and neutrophil function — effects that are magnified when these cells overexpress ACE. Macrophages that overexpress ACE are more effective against tumours and infections. Neutrophils that overexpress ACE have an increased production of superoxide, which increases their ability to kill bacteria. These effects are due to increased ACE activity but are independent of angiotensin II. ACE also affects the display of major histocompatibility complex (MHC) class I and MHC class II peptides, potentially by enzymatically trimming these peptides. Understanding how ACE expression and activity affect myeloid cells may hold great promise for therapeutic manipulation, including the treatment of both infection and malignancy.