Abstract
The (pro)renin-renin receptor, (P)RR has been claimed to be a novel element of the renin-angiotensin system (RAS). The function of (P)RR has been widely studied in renal and vascular pathology but the cardio-specific function of (P)RR has not been studied in detail. We therefore generated a transgenic mouse (Tg) with cardio-restricted (P)RR overexpression driven by the alpha-MHC promotor. The mRNA expression of (P)RR was ∼170-fold higher (P<0.001) and protein expression ∼5-fold higher (P<0.001) in hearts of Tg mice as compared to non-transgenic (wild type, Wt) littermates. This level of overexpression was not associated with spontaneous cardiac morphological or functional abnormalities in Tg mice. To assess whether (P)RR could play a role in cardiac hypertrophy, we infused ISO for 28 days, but this caused an equal degree of cardiac hypertrophy and fibrosis in Wt and Tg mice. In addition, ischemia-reperfusion injury was performed in Langendorff perfused isolated mouse hearts. We did not observe differences in parameters of cardiac function or damage between Wt and Tg mouse hearts under these conditions. Finally, we explored whether the hypoxia sensing response would be modulated by (P)RR using HeLa cells with and without (P)RR overexpression. We did not establish any effect of (P)RR on expression of genes associated with the hypoxic response. These results demonstrate that cardio-specific overexpression of (P)RR does not provoke phenotypical differences in the heart, and does not affect the hearts’ response to stress and injury. It is concluded that increased myocardial (P)RR expression is unlikely to have a major role in pathological cardiac remodeling.
Highlights
Therenin-renin receptor, (P)RR, was discovered and cloned in 2002 as a novel element of the renin-angiotensin system (RAS) [1]
To further study the effect of (P)RR overexpression on the heart, we analyzed a list of cardiac genes associated with cardiac hypertrophy and fibrosis, but did not observe differences between wild type (Wt) and transgenic mouse (Tg) mice
ISO in a dose of 35 mg/kg/BW for 28 days resulted in marked cardiac hypertrophy, as determined by the increase in left-ventricular weight (LV-W) to tibia length (TL), but no difference was observed between the groups
Summary
The (pro)renin-renin receptor, (P)RR, was discovered and cloned in 2002 as a novel element of the renin-angiotensin system (RAS) [1]. (P)RR has specific other functions in the assembly and function of vacuolar H+-ATPase (V-ATPase), an ATP-dependent proton pump which acidifies intracellular compartments [6]. Binding of both renin and its inactive precursor, prorenin, to the (P)RR exerts effects via angiotensin II-independent pathways, e.g.via second messengers including mitogen-activated protein kinases (MAPK) [2]. This has been shown to be associated with increased cell proliferation and upregulation of profibrotic genes [7]. It has been suggested that increased expression of (P)RR may be involved in renal and cardiac pathophysiology [7,11,12,13,14]
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