Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen

Müller, Dominik N.; Hilgers, Karl F.; Mathews, Salima; Breu, Volker; Fischli, Walter; Uhlmann, Regina; Luft, Friedrich C.

doi:10.1161/01.hyp.33.1.312

Cited by 15 publications

(15 citation statements)

References 48 publications

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“…However, in many instances a functional activity of prorenin in terms of angiotensin generation or effects on blood pressure could not be demonstrated. 33,34 In our hands and in accordance with these studies, uptake of glycosylated rat prorenin also did not increase intracellular angiotensin levels. Our data strongly indicate that internalization and its functional consequences are dependent on glycosylation of the protein: uptake of ren-2 d prorenin into the heart of TGR(mREN2)27 or Cyp1a1-ren-2 transgenic rats, as observed in our studies, required a mechanism independent from the mannose-6-phosphate receptor.…”

Section: Discussionsupporting

confidence: 90%

Functional Significance of Prorenin Internalization in the Rat Heart

Peters

Farrenkopf

Clausmeyer

et al. 2002

Circulation Research

114

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Abstract-Intracardiac renin is considered to be involved in the pathogenesis of cardiac hypertrophy, fibrosis, and myocardial infarction. Cardiac renin is predominantly derived from the circulation, because preprorenin is not expressed locally and uptake of renin has been demonstrated. One mechanism of internalization recently described involves the mannose-6-phosphate receptor and requires glycosylation of renin. Based on previous observations, we considered the existence of another pathway of uptake, not requiring glycosylation and predominantly involving prorenin. This hypothesis and its functional consequences were investigated in vitro and in vivo. We demonstrate that isolated adult cardiomyocytes internalize unglycosylated prorenin, which is followed by the generation of angiotensins. We further show that transgenic rats, expressing the ren-2 d renin gene in an inducible manner, exhibit markedly enhanced levels of unglycosylated renin within intracellular compartments in the heart as a consequence of the induction of hepatic transgene expression and the rise of circulating unglycosylated prorenin levels. Because in this model severe cardiac damage occurs as a consequence of the rise of circulating prorenin levels, internalization of prorenin into cardiac cells is likely to play a key role in this process.

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Section: Discussionsupporting

confidence: 90%

Functional Significance of Prorenin Internalization in the Rat Heart

Peters

Farrenkopf

Clausmeyer

et al. 2002

Circulation Research

114

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“…These findings support the idea that the high levels of prorenin often seen in diabetes actually contribute to tissue RAS activation, particularly in the vascular wall. When human recombinant prorenin was infused at 150 ng/ml (ϳ10 Ϫ9 M) into rats transgenic for human AGT, prorenin was not activated in tissue or in the circulation, and mean arterial pressure was neither increased nor decreased (23). This may be due to infusion of an insufficient amount of prorenin.…”

Section: Discussionmentioning

confidence: 99%

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Zhang

Noble

Border³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.

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“…Juxtaglomerular cells, the main source of circulating renin, secrete both active and inactive prorenin, but the inactive renin can be present at three to five times the level of active renin in the circulation of humans (15). The reason why these cells secrete large quantities of inactive enzyme is not clear, since prorenin appears not to be activated in the circulation (23,24) or to act as an endogenous antagonist for the effects of renin, at least in the vascular wall (25). The present results suggest that the main role of renin produced by mesangial cells may be the intracellular generation of angiotensin II, since only a minor quantity of active renin appears to be secreted by mesangial cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Andrade

Casarini

Schor

et al. 2002

Braz J Med Biol Res

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Renin is an enzyme involved in the stepwise generation of angiotensin II. Juxtaglomerular cells are the main source of plasma renin, but renin activity has been detected in other cell types. In the present study we evaluated the presence of renin mRNA in adult male Wistar rat and mouse (C-57 Black/6) mesangial cells (MC) and their ability to process, store and release both the active and inactive forms of the enzyme. Active renin and total renin content obtained after trypsin treatment were estimated by angiotensinogen consumption analyzed by SDS-PAGE electrophoresis and quantified by angiotensin I generation by HPLC. Renin mRNA, detected by RT-PCR, was present in both rat and mouse MC under basal conditions. Active renin was significantly higher (P<0.05) in the cell lysate (43.5 ± 5.7 ng h -1 10 6 cells) than in the culture medium (12.5 ± 2.5 ng h -1 10 6 cells). Inactive prorenin content was similar for the intra-and extracellular compartments (9.7 ± 3.1 and 3.9 ± 0.9 ng h -1 10 6 cells). Free active renin was the predominant form found in both cell compartments. These results indicate that MC in culture are able to synthesize and translate renin mRNA probably as inactive prorenin which is mostly processed to active renin inside the cell. MC secrete both forms of the enzyme but at a lower level compared with intracellular content, suggesting that the main role of renin synthesized by MC may be the intracellular generation of angiotensin II.

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Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen

Cited by 15 publications

References 48 publications

Functional Significance of Prorenin Internalization in the Rat Heart

Functional Significance of Prorenin Internalization in the Rat Heart

Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

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