Cardiac function and architecture are maintained in a model of cardiorestricted overexpression of the prorenin-renin receptor

PLoS One. 2014 Feb 25;9(2):e89929. doi: 10.1371/journal.pone.0089929. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Blotting, Western
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Creatine Kinase / metabolism
  • Echocardiography
  • Gene Expression Regulation / genetics*
  • HeLa Cells
  • Heart / physiology*
  • Humans
  • Hypoxia / metabolism
  • Isoproterenol
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Myocardium / metabolism*
  • Prorenin Receptor
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cell Surface / metabolism*
  • Reperfusion Injury / metabolism

Substances

  • Receptors, Cell Surface
  • L-Lactate Dehydrogenase
  • Creatine Kinase
  • Isoproterenol
  • Prorenin Receptor

Grants and funding

This work was supported by the Netherlands Heart Foundation (grant 2007T046) and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VENI, grant 916.10.117, and NWO VIDI, grant 917.13.350), all to Dr. de Boer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.