(Pro)renin Receptor Triggers Distinct Angiotensin II-Independent Extracellular Matrix Remodeling and Deterioration of Cardiac Function

Moilanen, Anne-Mari; Rysä, Jaana; Serpi, Raisa; Mustonen, Erno; Szabò, Zoltán; Aro, Jani; Näpänkangas, Juha; Tenhunen, Olli; Sutinen, Meeri; Salo, Tuula; Ruskoaho, Heikki

doi:10.1371/journal.pone.0041404

Cited by 41 publications

(31 citation statements)

References 45 publications

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“…Most importantly, our results have shown that the direct renin inhibitor aliskiren reduces the progression of VH and atherosclerosis in AngII-infused ApoE − / − mice at both sub-antihypertensive (10 mg/kg of body weight per day) and antihypertensive (50 mg/kg of body weight per day) doses. Recent work suggests that enhanced expression or activation of the PPR could have detrimental effects via AngII-independent mechanisms in both in vitro and in vivo studies [27,28]. In a relatively unique way, we focused on the efficacy of aliskiren in limiting complications of AngII infusion after the organ damage was established, rather than during this process, since this is likely to be most clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren limits abdominal aortic aneurysm, ventricular hypertrophy and atherosclerosis in an apolipoprotein-E-deficient mouse model

et al. 2014

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Aliskiren is a direct renin inhibitor developed to treat hypertension. Several clinical studies have suggested that aliskiren has beneficial effects on cardiovascular diseases beyond its antihypertensive effect. In the present study, we examined whether aliskiren limits the progression of AAA (abdominal aortic aneurysm), VH (ventricular hypertrophy) and atherosclerosis in an AngII (angiotensin II)-infused mouse model. ApoE-/- (apolipoprotein-E-deficient) mice were infused subcutaneously with AngII (1000 ng/kg of body weight per day; 4 weeks) to induce AAA and VH. At the completion of the AngII infusion, mice were randomly allocated to three groups to receive vehicle control, low-dose aliskiren (10 mg/kg of body weight per day) or high-dose aliskiren (50 mg/kg of body weight per day) for 4 weeks. Suprarenal aortic diameter assessed by ultrasound was significantly smaller in mice administered aliskiren at days 42 and 56. Aliskiren also significantly reduced the normalized heart weight, ventricular myocyte cell width and aortic arch atherosclerosis. Aliskiren lowered PRR (pro-renin receptor) expression and MAPK (mitogen-activated protein kinase) activity in the suprarenal aorta and heart. Aortic infiltration of T-lymphocytes and macrophages was reduced by aliskiren. In conclusion, aliskiren limits the progression of AAA, VH and atherosclerosis in an AngII-infused mouse model.

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Section: Discussionmentioning

confidence: 99%

Aliskiren limits abdominal aortic aneurysm, ventricular hypertrophy and atherosclerosis in an apolipoprotein-E-deficient mouse model

et al. 2014

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“…[3][4][5] On the other hand, increased PRR was observed in ischemic nephropathy, 6,7 glomerulosclerosis, 8 diabetic nephropathy, 9 diabetic retinopathy, 10 cardiac hypertrophy, 11 and heart failure. 12 In these models, the role of PRR was suggested, based on the use of a peptide that is supposed to block (pro)renin binding to PRR. But these results remain highly controversial.…”

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confidence: 99%

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Rosendahl

Niemann

Lange

et al. 2014

Laboratory Investigation

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Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken betaactin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25-to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.

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“…45 In contrast, overexpression of PRR in adult rat hearts via adenovirusmediated gene delivery for 2 weeks caused reduced left ventricular ejection fraction and resulted in Ang II-independent activation of cell signaling pathways. 52 Taken together, these studies suggest that either the cardiac PRR does not play a role in BP regulation or compensatory mechanisms counter any effects exerted by the increased PRR expression ( Figure 2).…”

Section: Role Of the Prr In Bp Regulationmentioning

confidence: 85%

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

Ramkumar

Kohan

2019

Kidney International

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The (pro)renin receptor (PRR) is a multifunctional protein that is expressed in multiple organs. Binding of prorenin/ renin to the PRR activates angiotensin II-dependent and angiotensin II-independent pathways. The PRR is also involved in autophagy and Wnt/ß catenin signaling, functions that are not contingent on prorenin binding. Emerging evidence suggests that the PRR plays an important role in blood pressure regulation and glucose and lipid metabolism. Herein, we review PRR function in health and disease, with particular emphasis on hypertension and the metabolic syndrome.

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(Pro)renin Receptor Triggers Distinct Angiotensin II-Independent Extracellular Matrix Remodeling and Deterioration of Cardiac Function

Cited by 41 publications

References 45 publications

Aliskiren limits abdominal aortic aneurysm, ventricular hypertrophy and atherosclerosis in an apolipoprotein-E-deficient mouse model

Aliskiren limits abdominal aortic aneurysm, ventricular hypertrophy and atherosclerosis in an apolipoprotein-E-deficient mouse model

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

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