Abstract 16491: Studies of the Localization and Functional Significance of the Cardiac (pro)renin Receptor
Background: The prorenin/renin or pro(renin) receptor [(P)RR] is a 350 amino acid transmembrane protein, that on ligand binding, increases the catalytic efficiency of angiotensinogen cleavage by both prorenin and renin, resulting in augmented angiotensin I formation at the cell surface. While implicated in a broad range of diseases, most studies to date have focused on the kidney, particularly in the diabetic context.
Objectives: We sought to examine the site-specific expression of (P)RR within the heart.
Methods: Using a combination of confocal microscopy, site specific markers and transmission electron microscopy we assessed the location of the (P)RR at both a cellular and sub cellular level. We also assessed the abundance of (P)RR expression in the setting of disease, using the transgenic m(Ren2)-27 diabetic rat, a model of diabetic cardiomyopathy, and assessed the effects of cardiac protection using direct renin inhibition on (P)RR expression.
Results: we determined that (P)RR is found predominantly at the Z-disc and dyad of cardiac myocytes (arrows-figure 1) coinciding closely with the distributions of the vacuolar H+−ATPase and ryanodine receptor (coefficient of localization 0.34), known to be located within T-tubules and the sarcoplasmic reticulum's terminal cisternae, respectively. (P)RR mRNA and protein abundance were both increased approximately 3-fold in the hearts of diabetic (mRen-2)−27 rats in association with diastolic dysfunction, cardiac myocyte hypertrophy and interstitial fibrosis. Blockade of the renin-angiotensin system with the direct renin inhibitor, aliskiren, reduced cardiac (P)RR expression in association with improvements in cardiac structure and function.
Conclusion: Together, these findings are consistent with the notion that (P)RR is a component of the vacuolar H+−ATPase, and that like the latter, it is increased in the setting of cardiac stress and lowered by the administration of an ostensibly cardio protective agent.
- © 2010 by American Heart Association, Inc.