Abstract 16027: Low-dose Clofibrate Protects the Heart and Kidney in the 5/6 NX Model of Chronic Kidney Disease

Abstract

Cardiovascular related disease and/or events are the leading single cause of death in patients with chronic kidney disease (CKD), yet the pathological mechanisms involved are not well understood. We have previously reported that the 5/6 nephrectomy (5/6 NX) rat model of CKD exhibits left ventricle (LV) dilation, reduced function, and increased miR-21 levels 7 weeks post-surgery. Suppression of miR-21 prevented LV dilation and improved cardiac function, at least in part, by upregulation of target peroxisome proliferator-activated receptor alpha (PPARα). The focus of this study was to evaluate the therapeutic potential of clofibrate (CLO), a PPARα agonist, in the 5/6 NX model. We hypothesized that low-dose CLO treatment would reduce cardiac dysfunction in 5/6 NX rats. To test this, we performed 5/6 NX or sham surgery on 10 week old male Sprague Dawley rats. Left ventricular remodeling and function was evaluated by echocardiography prior to surgery and bi-weekly thereafter, throughout the 10 week study. Renal function was monitored by 24 hour urine and plasma creatinine measurements at those time points. We administered CLO (25 mg/kg/day i.p., roughly 1/10 the dose commonly used in rats) to a subset of animals (n=4-6/group) beginning 5 weeks post-5/6 NX. We found that 5/6 NX rats developed progressive LV dilation and impaired function over the 10 week study. Treatment with CLO completely prevented LV dilation and normalized wall thickness. Further, CLO treatment significantly increased % fractional shortening (47.9±6.0 CLO vs. 32.6±1.7 5/6 NX control, p<0.05, ANOVA). With 10 weeks of 5/6 NX proximal convoluted tubules exhibited a loss of brush border, severe dilation of the tubules, and extensive epithelial shedding. Treatment of 5/6 NX rats with CLO largely prevented these changes. Despite this improvement in tubular morphology, plasma creatinine levels were not different than 5/6 NX controls. In conclusion, we find that low-dose CLO treatment initiated during progressive kidney disease is both cardio- and reno-protective. Our data suggest that PPARα agonists may be an effective therapeutic intervention in established CKD.