SO076EVOLOCUMAB HAS THERAPEUTIC EFFECTS ON EXPERIMENTAL MODEL OF FSGS

Abstract

Abstract Background and Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9), which accelerates LDL-receptor degradation, plays a central role in dyslipidemia in nephrotic syndrome (NS). Intracellular LDL-C accumulation is supposed to damage podocytes through oxidative stress, foam cell formation, and apoptosis. In the present study, we investigate the effects of evolocumab (EVO), which is anti-PCSK9 monoclonal antibody, on a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with NS in order to clarify the potential of EVO as a therapeutic agent in FSGS. Method Male BALB/c mice aged 9 to 11 weeks were divided into vehicle and intervention groups. The mice underwent subcutaneous injection of normal saline (FSGS-Vehicle group) or EVO (30 mg/kg) (FSGS-EVO group) and immediately after that, they were administered adriamycin (11.5 mg/kg) from tail vein. All mice were sacrificed on Day 14, and then morphological and functional analyses were performed. Results EVO treatment significantly reduced serum levels of LDL-C (mg/dl, 305.3±77.1 vs. 159.1±31.7, p<0.01) and PCSK9 (ng/ml, 652.9±230.0 vs 311±116.5, p<0.001). In addition, EVO treatment significantly improved renal function, including albuminuria (albumin/creatinine (Cr), 15.73±1.26 vs. 7.32±1.02, p<0.001), serum Cr (mg/dl, 0.48±0.13 vs. 0.18±0.044, p<0.001) and BUN (mg/dl, 80.08±20.22 vs. 46.86±9.60, p<0.05). Compatibly with the clinical data, the severity of glomerulosclerosis score (semi-quantification, 2.44 vs. 1.95, p<0.001) was ameliorated and podocyte density (number of podocyte/glomerulus, 2.61 vs. 7.54, p<0.001) was maintained in the FSGS-EVO mice compared with the FSGS-Vehicle mice. Conclusion Our findings provided novel insights into the protective effects of EVO on adriamycin nephropathy, indicating EVO as a potent therapeutic agent for FSGS.