Background: The pro(renin) receptor is a 350 amino acid transmembrane protein, that on ligand binding, increases the catalytic efficiency of angiotensinogen cleavage by both prorenin and renin, augmenting angiotensin I formation at the cell surface. While implicated in a broad range of diseases, studies to date have focused on the kidney, particularly in the diabetic context. We sought to examine the site-specific expression of the pro(renin) receptor within the heart.
Methods: Using confocal microscopy, site-specific markers and transmission electron microscopy we assessed the location of the pro(renin) receptor in the heart at both cellular/sub-cellular levels. We assessed pro(renin) receptor expression in the setting of disease and blockade of the renin-angiotensin system, using the TGR[m(Ren2)-27] model of diabetic cardiomyopathy and the direct renin inhibitor, aliskiren.
Results: The pro(renin) receptor was found predominantly at the Z-disc and dyad of cardiac myocytes coinciding closely with the distributions of the vacuolar H⁺-ATPase and ryanodine receptor, known to be located within T-tubules and the sarcoplasmic reticulum's terminal cisternae, respectively. Pro(renin) receptor mRNA/protein abundance were increased ∼3-fold in the hearts of diabetic rats in association with diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis (all P < 0.01). Direct renin inhibition reduced cardiac pro(renin) receptor expression in association with improved cardiac structure/function (all P < 0.05).
Conclusion: Together, these findings are consistent with the notion that the pro(renin) receptor is a component of the vacuolar H⁺-ATPase, and that like the latter, is increased in the setting of cardiac stress and lowered by the administration of an ostensibly cardioprotective agent.