H(P)RRs preferentially bind prorenin, and such binding results in angiotensin generation, most likely because binding results in prorenin activation.

Abstract-Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentrationdependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (nϭ4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (PϽ0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensinindependent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression. (Hypertension. 2006;48:564-571.)

Abstract-We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202Ϯ4 mm Hg), serum creatinine, and albuminuria (34Ϯ5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115Ϯ6 and 139Ϯ5 mm Hg) and albuminuria (0.4Ϯ0.1 and 1.6Ϯ0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148Ϯ4 mm Hg) and albuminuria (2.1Ϯ0.7 mg per day), low-dose Val reduced BP (182Ϯ3 mm Hg) and albuminuria (24Ϯ3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4Ϯ0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and ␤-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR. Key Words: renin Ⅲ rats, transgenic Ⅲ hypertrophy R enin is the rate-limiting step in the generation of angiotensin II (Ang II). 1 Thus, inhibiting this step reduces Ang II levels. Historically, renin inhibitors have not been clinically successful because of lack of potency or bioavailability. The new nonpeptidic renin inhibitor aliskiren is a potent human renin inhibitor (IC 50 ϭ0.6 nmol/L). 2 Because renin displays species specificity for its substrate, human renin inhibitors cannot be tested efficiently in conventional hypertensive rat models. To circumvent this problem, transgenic rats and mice were developed harboring the human renin and the human angiotensinogen genes. 3,4 Human renin does not effectively cleave rat angiotensinogen, and similarly, rat renin cleaves human angiotensinogen poorly. 5 Consequently, the single transgenic rats and mice (ie, transgenic for either human angiotensinogen or renin) are normotensive. However, when cross-bred, the double transgenic rat (dTGR) offspring develop hypertension with severe organ damage and do not live beyond the seventh or eighth week of age. We extensively studied these animals; the injury features nuclear factor B (NF-B) and activator protein-1 transcription factor activation, upregulation of surface adhesion molecules, cytokines, and the influx of inflammatory cells. 6 ...

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.

Background-Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. Methods and Results-Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (nϭ30), patients requiring LVAD support (nϭ16; LVAD duration, 145Ϯ33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (PϽ0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (PϽ0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. Conclusions-LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes. (Circulation. 2005;112:364-374.)Key Words: cardiomyopathy Ⅲ collagen Ⅲ heart-assist devices Ⅲ heart failure Ⅲ metalloproteinases L eft ventricular assist devices (LVADs) provide mechanical support for the end-stage failing human heart and have been used as a bridge to cardiac transplantation. We have demonstrated that LVAD support is associated with normalization of diastolic chamber properties as indexed by the passive pressure-volume relation. [1][2][3] This normalization of diastolic properties results from a regression of myocyte hypertrophy, including reduced LV mass, wall thickness, and myocyte diameter. 4,5 In addition, LVAD support has been associated with a trend toward normalization in cardiomyocyte function, 6 calcium cycling properties, 7 and expression of various genes. 8 In addition to changes in intrinsic myocardial properties, LVAD use is associated with changes in the characteristics and metabolism of the extracellular matrix (ECM). However, unlike almost all other aspects of reverse remodeling of the myocardium and ventricular chamber, the ECM changes do not uniformly reflect a return toward normal conditions. 9 -11...

Background-Angiotensin (Ang) II type 2 (AT 2 ) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT 2 receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs). Methods and Results-HCMAs (diameter, 160 to 500 m) were obtained from 49 heart valve donors (age, 3 to 65 years).Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC 50 , 8.6Ϯ0.2; maximal effect [E max ], 79Ϯ13% of the contraction to 100 mmol/L K ϩ ). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT 2 receptor antagonist PD123319 increased E max to 97Ϯ14% (PϽ0.05). The increase in E max was larger in older donors (correlation ⌬E max versus age, rϭ0.47, PϽ0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B 2 ) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49Ϯ16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT 2 receptors in HCMAs. Conclusions-AT 2 receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B 2 receptors and NO. Most likely, AT 2 receptors are located on endothelial cells, and their contribution increases with age.

P reeclampsia is a pregnancy-related disorder, clinically characterized by the new onset of proteinuria and hypertension in the second half of pregnancy, with a great effect on maternal and fetal morbidity and mortality worldwide. 1A better understanding of the pathogenic mechanisms underlying preeclampsia might help identifying biomarkers that allow early diagnosis and treatment of preeclampsia. Recently, disturbances in angiogenic balance (favoring antiangiogenic over proangiogenic factors), elevated endothelin-1 (ET-1) levels, and a suppressed renin-angiotensin-aldosterone system (RAAS) have been reported. [2][3][4] As a consequence, the ratio of the antiangiogenic soluble Fms-like tyrosine kinase-1 (sFlt-1) and the proangiogenic placental growth factor (PlGF) is now thought to be a reliable biomarker for the diagnosis of preeclampsia. 5 In fact, patients with a ratio ≥85 have a poor pregnancy outcome independent of their clinical diagnosis compared with patients with a ratio <85. 5Of interest, treatment of cancer patients with antiangiogenic drugs (which, like sFlt-1, prevent the actions of vascular endothelial growth factor [VEGF]) resulted in hypertension, proteinuria, renin suppression, and elevated ET-1 levels. 6 Animal studies with antiangiogenic drugs additionally revealed that the renal histological changes observed during such treatment, in particular glomerular endotheliosis, resembled the renal alterations observed in preeclampsia. 7 From the observation that the dual ET A/B receptor antagonist macitentan prevented both the rise in blood pressure and proteinuria during Abstract-Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and reninangiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomer...

The increased urinary renin levels in diabetes and the decreased urinary renin levels following RAAS blockade, occurring independently of changes in plasma renin, reflect the activated renal RAAS in diabetes and the success of RAAS blockade in the kidney, respectively. Urinary renin, therefore, more closely reflects renal RAAS activity than urinary angiotensinogen or aldosterone.