Characterization of the Intrarenal Renin-Angiotensin System in Experimental Alport Syndrome

Bae, Eun Hui; Konvalinka, Ana; Fang, Fei; Zhou, Xiao‐Hua; Williams, Vanessa; Maksimowski, Nicholas; Song, Xuewen; Zhang, Shaoling; John, Rohan; Oudit, Gavin Y.; Pei, York; Scholey, James W.

doi:10.1016/j.ajpath.2015.01.021

Cited by 26 publications

(33 citation statements)

References 38 publications

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“…Dried samples were reconstituted with the EIA buffer provided by the manufacturer and assayed for angiotensin II as previously described. 41 Renal angiotensin II content was expressed as fmol of angiotensin II per g of kidney.…”

Section: Methodsmentioning

confidence: 99%

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

Giani

Eriguchi

Bernstein

et al. 2017

Kidney International

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Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension.

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Section: Methodsmentioning

confidence: 99%

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

Giani

Eriguchi

Bernstein

et al. 2017

Kidney International

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“…This notion is further emphasized by the recent discovery of MrgD as another novel receptor for Ang- (1-7) regulating the physiological arterial pressure. 9 Physiological relevance of the Ang-(1-7)/AT1-R axis could be, however, questioned given that the affinity/potency of Ang-(1-7) for AT1-R is modest (≈300 nmol/L) and relatively far from plasma concentrations generally described, with significant differences in between rodents (nmol/L) 26,27 or human species (pM). [28][29][30] Nevertheless, despite the RAAS was originally described as a circulating system, it is now widely accepted that a distinct local RAAS does exist in several tissues, 31 thus promoting a close ligand-receptor proximity to ensure an accurate spatiotemporal regulation of RAAS actions similar to that observed for neurotransmitters concentrations in the synaptic cleft after release.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

et al. 2016

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Hyperactivity of the renin–angiotensin–aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin–angiotensin–aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1–7) in AT1-R–expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1–7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin–angiotensin–aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1–7) a known Mas receptor-specific ligand, as an AT1-R–biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1–7) at AT1-R, similar to that of synthetic AT1-R–biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1–7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1–7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin–angiotensin–aldosterone system.

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“…Thus, blockade or RAAS would be expected to reduce glomerular blood pressure, which is why RAAS blockade reduces proteinuria and slows renal disease progression for a large number of renal diseases [36]. The RAAS system is complex, and angiotensin II can have a number of direct effects in addition to vasoconstriction, including induction of chemokines and reactive oxygen species and well as extracellular matrix homeostasis [37]. Beyond its effects on blood pressure, these influences need to be considered when evaluating the renoprotective effects of RAAS blockade on Alport renal disease.…”

Section: What We Know About the Mechanism Of Alport Glomerular Diseasmentioning

confidence: 99%

“…Along these lines, angiotensin II has been found to be up-regulated in Alport mice, while expression of angiotensin 1–7 was reduced. In addition, both angiotensinogen and renin expression levels were increased in Alport mice [37]. This modulation of the renin/angiotensin components must also be considered when evaluating the molecular effects of RAAS blockade on Alport renal pathology.…”

Section: What We Know About the Mechanism Of Alport Glomerular Diseasmentioning

confidence: 99%

Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome

Cosgrove

Liu²

2017

Matrix Biology

104

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Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients.

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Characterization of the Intrarenal Renin-Angiotensin System in Experimental Alport Syndrome

Cited by 26 publications

References 38 publications

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome

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