Abstract 18065: The Upregulation of MicroRNA miR-21 Mediates Concentric Left Ventricle Remodeling in a Rat Model of Chronic Renocardiac Syndrome

Abstract

Chronic kidney disease (CKD) puts patients at a greatly increased risk of cardiovascular disease in a condition termed chronic renocardiac syndrome (RCS). We have utilized the 5/6 nephrectomy (5/6 NX) model in Sprague Dawley rats to study the gradual development of cardiac dysfunction resulting from declining kidney function. Previously, we identified alterations in several microRNAs (miRNAs) in left ventricle (LV) tissue 7 weeks after 5/6 NX surgery. We hypothesized that the upregulation of miR-21 in the LV following 5/6 NX contributes to LV pathology, rather than being a consequence of it. In situ hybridization revealed that miR-21 expression in the LV of 5/6 NX animals is highest in regions of perivascular fibrosis. To study the impact of miR-21 on LV remodeling and function, we delivered locked-nucleic acid (LNA) modified anti-miR-21 or anti-scrambled-miR (Exiqon, delivered i.v. at 1 mg/kg) to 5/6 NX animals (n=6/group) in 3 sequential days at 1 week post-surgery, and again 4 weeks post-surgery. Echocardiography was performed prior to 5/6 NX surgery and bi-weekly thereafter, throughout the 7 week study, to evaluate remodeling and function (anti-miR-21 vs. anti-scramble treated for all comparisons). The average LV miR-21 expression was reduced nearly 12-fold with anti-miR-21 treatment when measured 7 weeks post-5/6 NX. Anti-miR-21 treatment preserved stroke volume and fractional shortening between weeks 3 and 5 post-5/6 NX while both functional indices declined in anti-scramble treated rats. Additionally, concentric LV remodeling (LV wall hypertrophy and reduced chamber diameter) 5 weeks post-5/6 NX was completely prevented with anti-miR-21 treatment. At 7 weeks post-5/6 NX, when LV decompensation is evident in untreated rats, anti-miR-21 treatment maintained LV wall thickness and chamber diameter while fractional shortening was significantly increased (p <0.05). Anti-miR-21 treatment had no effect on blood pressure. We conclude that chronic knockdown of miR-21 in the 5/6 NX model prevented pathological concentric remodeling. Together these data suggest that the upregulation of cardiac miR-21 following 5/6 NX is an important mediator of pathological cardiac remodeling and dysfunction.