Hemodynamic, hormonal, and renal effects of (pro)renin receptor blockade in experimental heart failure.
ABSTRACT Background- The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Methods and Results- Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. Conclusions- (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.
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ABSTRACT: The present study was designed to investigate the physiological roles of renin/prorenin receptor in cultured rat mesangial cells. The presence of renin/prorenin receptor in mesangial cells was determined by immunofluorescence staining, real-time quantitative reverse transcriptase-polymerase chain reaction (real-time PCR) and Western blotting assay. The expression of renin/prorenin receptors was identified in both rat renal slices and cultured mesangial cells. Meanwhile, the cultured mesangial cells were demonstrated synthesizing and secreting (Pro)renin as well. Knockdown of renin/prorenin receptor expression was performed by small interfering RNA (siRNA) transfection. Either knockdown or blockade of renin/prorenin receptor by handle region peptide (HRP) reduced mesangial cell proliferation. In the meantime, release of type IV collagen, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and mRNA level of transforming growth factor-β1 (TGF-β1) were decreased. On the other hand, both the production and activity of matrix metalloproteinase-2, a key enzyme to degrade type IV collagen, was increased. The present results indicated that renin/prorenin receptor played a regulatory role in mesangial cells proliferation and extracellular matrix accumulation. Blockade of renin/prorenin receptors may postpone over extracellular accumulation, which occurs in some pathological situations, via suppressed both mesangial cell proliferation and fibrotic factor release.European journal of pharmacology 03/2009; · 2.59 Impact Factor
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ABSTRACT: Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin-angiotensin system, was associated with organ damage in the kidney. However, there has been little information for (P)RR in hearts. To investigate the regulation of (P)RR in heart failure, we examined the expression of (P)RR in hearts and kidneys of rats with congestive heart failure (CHF) due to coronary ligation by quantitative RT-PCR and immunohistochemistry. Significantly increased levels of (P)RR mRNA were found in the atrium, right ventricle, non-infarcted part of left ventricle, infarcted part of left ventricle and kidney of CHF rats, when compared with sham operated rats (about 1.6-fold, 1.4-fold, 1.6-fold, 1.7-fold and 1.5-fold, respectively). Expression levels of mRNAs encoding renin and angiotensinogen in these heart and kidney tissues were also increased in the CHF rats. Immunohistochemistry showed positive (P)RR immunostaining in the myocardium, the renal tubular cells, and vascular smooth muscle and endothelial cells in the heart and the kidney. The renal tubular cells were more intensely immunostained in CHF rats than in sham operated rats. These findings suggest that the expression of (P)RR is increased in the hearts and kidneys of rats with heart failure, and that (P)RR may contribute to heart failure.Peptides 09/2009; 30(12):2316-22. · 2.61 Impact Factor
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ABSTRACT: Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8+/-5 versus 118.9+/-3.7 mm Hg; P=0.008), and an augmentation in heart rate (349.1+/-7.7 versus 303.1+/-16.16 bpm; P=0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428+/-64.9 versus 207.3+/-73.24 pg/mL in control; P=0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04+/-2.2 versus 2.8+/-0.55 in control; P=0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).Hypertension 04/2006; 47(3):552-6. · 7.63 Impact Factor