scholarly journals Inhibition of Endocytosis of Clathrin-Mediated Angiotensin II Receptor Type 1 in Podocytes Augments Glomerular Injury

2019 ◽  
Vol 30 (12) ◽  
pp. 2307-2320 ◽  
Author(s):  
Kazunori Inoue ◽  
Xuefei Tian ◽  
Heino Velazquez ◽  
Keita Soda ◽  
Zhen Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Knockout Mice ◽  
Renin Angiotensin System ◽  
Membrane Dynamics ◽  
Receptor Type ◽  
Angiotensin Ii Receptor ◽  
Double Knockout ◽  
Angiotensin System ◽  
Renin Angiotensin

BackgroundInhibition of the renin-angiotensin system remains a cornerstone in reducing proteinuria and progression of kidney failure, effects believed to be the result of reduction in BP and glomerular hyperfiltration. However, studies have yielded conflicting results on whether podocyte-specific angiotensin II (AngII) signaling directly induces podocyte injury. Previous research has found that after AngII stimulation, β-arrestin–bound angiotensin II receptor type 1 (AT1R) is internalized in a clathrin- and dynamin-dependent manner, and that Dynamin1 and Dynamin2 double-knockout mice exhibit impaired clathrin-mediated endocytosis.MethodsWe used podocyte-specific Dyn double-knockout mice to examine AngII-stimulated AT1R internalization and signaling in primary podocytes and controls. We also examined the in vivo effect of AngII in these double-knockout mice through renin-angiotensin system blockers and through deletion of Agtr1a (which encodes the predominant AT1R isoform expressed in kidney, AT1aR). We tested calcium influx, Rac1 activation, and lamellipodial extension in control and primary podocytes of Dnm double-knockout mice treated with AngII.ResultsWe confirmed augmented AngII-stimulated AT1R signaling in primary Dnm double-knockout podocytes resulting from arrest of clathrin-coated pit turnover. Genetic ablation of podocyte Agtr1a in Dnm double-knockout mice demonstrated improved albuminuria and kidney function compared with the double-knockout mice. Isolation of podocytes from Dnm double-knockout mice revealed abnormal membrane dynamics, with increased Rac1 activation and lamellipodial extension, which was attenuated in Dnm double-knockout podocytes lacking AT1aR.ConclusionsOur results indicate that inhibiting aberrant podocyte-associated AT1aR signaling pathways has a protective effect in maintaining the integrity of the glomerular filtration barrier.

scholarly journals The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 650
Author(s):  
Babak Saravi ◽  
Zhen Li ◽  
Corinna N. Lang ◽  
Bonaventura Schmid ◽  
Frauke K. Lang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Human Diseases ◽  
Receptor Type ◽  
Angiotensin Ii Receptor ◽  
Inflammatory Pathway ◽  
Angiotensin System ◽  
Regulatory Pathways ◽  
Renin Angiotensin ◽  
Positive Effects

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1–7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.

A Review of Angiotensin Receptor Blocker-based Therapies at all Levels of Cardiovascular Risk

2011 ◽  
Vol 7 (4) ◽  
pp. 254 ◽  
Author(s):  
Giuliano Tocci ◽  
Lorenzo Castello ◽  
Massimo Volpe ◽  
◽  
◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ventricular Hypertrophy ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Clinical Settings ◽  
Angiotensin Ii Receptor ◽  
Angiotensin System ◽  
Receptor Blockers ◽  
Artery Disease

The renin–angiotensin system (RAS) has a key role in the maintenance of cardiovascular homeostasis, and water and electrolyte metabolism in healthy subjects, as well as in several diseases including hypertension, left ventricular hypertrophy and dysfunction, coronary artery disease, renal disease and congestive heart failure. These conditions are all characterised by abnormal production and activity of angiotensin II, which represents the final effector of the RAS. Over the last few decades, accumulating evidence has demonstrated that antihypertensive therapy based on angiotensin II receptor blockers (ARBs) has a major role in the selective antagonism of the main pathological activities of angiotensin II. Significant efforts have been made to demonstrate that blocking the angiotensin II receptor type 1 (AT1) subtype receptors through ARB-based therapy results in proven benefits in different clinical settings. In this review, we discuss the main benefits of antihypertensive strategies based on ARBs in terms of their efficacy, safety and tolerability.

Localization of angiotensin II receptor and local renin-angiotensin system in human colonic mucosa

2001 ◽  
Vol 120 (5) ◽  
pp. A313-A314
Author(s):  
Koki Hirasawa ◽  
Yoshihiko Sato ◽  
Yoshisuke Hosoda ◽  
Tatsuo Yamamoto ◽  
Hiroyuki Hanai
Keyword(s):  
Angiotensin Ii ◽  
Colonic Mucosa ◽  
Renin Angiotensin System ◽  
Angiotensin Ii Receptor ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Renin-Angiotensin System Blockers and the COVID-19 Pandemic

Hypertension ◽  
2020 ◽  
Vol 75 (6) ◽  
pp. 1382-1385 ◽  
Author(s):  
A.H. Jan Danser ◽  
Murray Epstein ◽  
Daniel Batlle
Keyword(s):  
Angiotensin Ii ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Receptor Blockers ◽  
Renin Angiotensin System Blockers

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.

scholarly journals Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice

2018 ◽  
Vol 6 (6) ◽  
pp. 955-960 ◽  
Author(s):  
Sameh Saber ◽  
Amr Mahmoud ◽  
Noha Helal ◽  
Eman El-Ahwany ◽  
Rasha Abdelghany
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Rank Test ◽  
Protective Effects ◽  
Angiotensin Ii Receptor ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin

BACKGROUND: Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC).OBJECTIVE: We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC.METHODS: HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups.RESULTS: The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice.CONCLUSION: Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies.

Sign in / Sign up

Export Citation Format

Share Document