Abstract 6248: The Direct Renin Inhibitor, Aliskiren, Improves Cardiac Function Via Direct Renin Inhibition And Via Renin Receptor Modulation In A Rodent Model Of Diabetic diastolic heart failure.
Background: Heart failure, a common cause of morbidity and mortality in diabetic patients, is traditionally treated by ACE inhibitors and ARBs, agents that block the renin-angiotensin system (RAS). The efficacy of a new class of RAS blockers, the direct renin inhibitors (DRIs) is, however, uncertain as is the potential role of the recently described (pro)renin receptor (PRR) that activates MAP Kinase and is postulated to mediate organ injury. Accordingly, we sought to determine the effectiveness of DRI and examine its effects on PRR expression.
Methods: In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Animals were randomized to receive either vehicle or aliskiren (10mg/kg/day via osmotic mini-pump) and followed for 6 weeks. Cardiac function was assessed by echocardiography and pressure-volume loop acquisition. The H9C2 cell line was used for cell culture studies.
Results: Aliskiren treated diabetic animals demonstrated improved diastolic function when compared to untreated diabetic rats. Systolic function was preserved across groups (see table⇓). Collagen deposition and cardiomyocyte diameter were also reduced in aliskiren treated animals (both p<0.01). Expression of renin receptor mRNA in-vivo was increased in diabetes, and reduced by treatment with aliskiren (all p<0.05). Prorenin stimulation of H92C cells led to ERK phosphorylation (p<0.05). Aliskiren treatment had no effect on ERK phosphorylation, renin receptor total protein nor mRNA.
Conclusion: Aliskiren prevented the development of structural and functional changes of diastolic heart failure in the diabetic Ren-2 rat. The mechanisms underlying the over-expression of PRR in diabetic rat hearts and the response to aliskiren in vivo but not in vitro are uncertain but raise the possibility that up-regulation of PRR expression may be a response to injury that is lessened by DRI.