Renin and Prorenin Activate Pathways Implicated in Organ Damage in Human Mesangial Cells Independent of Angiotensin II Production

Ra, Melnyk; J, Tam; Boie, Yves; Bp, Kennedy; Percival,

doi:10.1159/000220260

Cited by 22 publications

(17 citation statements)

References 53 publications

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“…Among them, we suggest that the acute changes of systemic hemodynamics in ADHF patients might influence PRA before changing entire RAAS activation. Furthermore, recent experimental studies have raised the possibility that the (pro-) renin receptor plays pathological roles in the progression of HF [30,31]. Recent studies also suggest that there are multiple and complex pathways regulating RAAS activation, which are related to cortisol [32], parathyroid hormone [33] and inflammation [34].…”

Section: Renin-angiotensin-aldosterone System Factors In Adhf Patientsmentioning

confidence: 99%

The predictability of renin–angiotensin–aldosterone system factors for clinical outcome in patients with acute decompensated heart failure

et al. 2015

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Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p < 0.01) and medication such as RAAS blockers (HR: 1.03, CI [1.01-1.05], p < 0.01), whereas PAC was borderline-significant (univariate analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events.

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Section: Renin-angiotensin-aldosterone System Factors In Adhf Patientsmentioning

confidence: 99%

The predictability of renin–angiotensin–aldosterone system factors for clinical outcome in patients with acute decompensated heart failure

et al. 2015

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“…It was shown that both have a similar transcriptional signature that is independent of Ang production. Importantly, the changes in gene expression induced by renin and pro-renin were consistent with the development of organ damage and fibrosis, primarily through TGF-b mechanisms [32].…”

Section: Pulmonary Fibrosis E Montes Et Almentioning

confidence: 74%

Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis

Eduardo¹,

Ruiz²,

Checa³

et al. 2011

Eur Respir J

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The pathogenesis of idiopathic pulmonary fibrosis (IPF) is probably the result of interplay between cytokines/chemokines and growth factors. The renin-angiotensin (Ang) system is involved, although its profibrotic effect is attributed to Ang II. However, recent studies suggest that renin, through a specific receptor, is implicated in fibrogenesis.In this study, the expression of renin and renin receptor was examined in normal and IPF lungs and fibroblasts. Normal human lung fibroblasts were stimulated with renin or transfected with renin small interfering RNA (siRNA), and the expression of transforming growth factor (TGF)-b1 and a-1-type I collagen was analysed.Normal lungs and lung fibroblasts expressed renin, which was strongly upregulated in IPF lungs and fibroblasts (,10-fold increase; p,0.05). Immunocytochemistry showed intense renin staining in IPF fibroblasts. Renin-stimulated lung fibroblasts displayed an increase in the expression of TGF-b1 (mean¡SD 1. p,0.01), while knocking down renin expression using siRNA provoked a strong decrease of both molecules. These effects were independent of Ang II, since neither losartan nor captopril decreased these effects. Renin also decreased matrix metalloprotease-1 expression and induced TGF-b1 activation (163¡34 versus 110¡15 pg active TGF-b1 per mg total protein). These findings highlight the possible role of renin as an Ang II-independent profibrotic factor in lung fibrosis.

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“…Melnyk et al [83], by performing a gene expression profiling study in human mesangial cells, found that 20 nmol/l renin and 50 nmol/l prorenin (in the presence of 10 mmol/l M6P to block M6P/IGFII receptors) activated pathways implicated in organ damage. Among others, COX-2 up-regulation was observed.…”

Section: Kidney and Diabetesmentioning

confidence: 99%

(Pro)renin and its receptors: pathophysiological implications

Batenburg

Danser

2012

Clinical Science

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Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin [together denoted as (pro)renin]. Since tissue renin levels are usually somewhat higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. Several candidates have been evaluated in the past three decades, including a renin-binding protein, the mannose 6-phosphate/insulin-like growth factor II receptor and the (pro)renin receptor. Although the latter seemed the most promising, its nanomolar affinity for renin and prorenin is several orders of magnitude above their actual (picomolar) levels in blood, raising doubt on whether (pro)renin-(pro)renin receptor interaction will ever occur in vivo. A wide range of in vitro studies have now demonstrated (pro)renin-receptor-induced effects at nanomolar renin and prorenin concentrations, resulting in a profibrotic phenotype. In addition, beneficial in vivo effects of the putative (pro)renin receptor blocker HRP (handle region peptide) have been observed, particularly in diabetic animal models. Despite these encouraging results, many other studies have reported either no or even contrasting effects of HRP, and (pro)renin-receptor-knockout studies revealed lethal consequences that are (pro)renin-independent, most probably due to the fact that the (pro)renin receptor co-localizes with vacuolar H+-ATPase and possibly determines the stability of this vital enzyme. The present review summarizes all of the recent findings on the (pro)renin receptor and its blockade, and critically compares it with the other candidates that have been proposed to mediate (pro)renin uptake from blood. It ends with the conclusion that the (pro)renin-(pro)renin receptor interaction, if it occurs in vivo, is limited to (pro)renin-synthesizing organs such as the kidney.

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Renin and Prorenin Activate Pathways Implicated in Organ Damage in Human Mesangial Cells Independent of Angiotensin II Production

Cited by 22 publications

References 53 publications

The predictability of renin–angiotensin–aldosterone system factors for clinical outcome in patients with acute decompensated heart failure

The predictability of renin–angiotensin–aldosterone system factors for clinical outcome in patients with acute decompensated heart failure

Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis

(Pro)renin and its receptors: pathophysiological implications

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