Abstract 500: Silencing Apolipoprotein C3 Prevents Diabetic Kidney Disease And Atherosclerosis In A Mouse Model Of Type 2 Diabetes

Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a small apolipoprotein that is elevated by insulin-insufficiency and regulates plasma triglyceride levels. To test if APOC3, and the dyslipidemia it represents, play a role in diabetic kidney disease (DKD) and associated atherosclerosis, we treated BTBR wildtype (WT) and leptin-deficient (OB; diabetic) mice with an antisense oligonucleotide (ASO) to APOC3 or a control ASO (cASO), all in the setting of human-like dyslipidemia (accomplished by administration of an ASO targeting the LDLR). APOC3 ASO treatment reduced triglycerides, triglyceride-rich lipoproteins. It prevented diabetes-accelerated atherosclerosis in the aortic sinus, brachiocephalic artery, and aorta (sinus lesion: 67926 ± 8486 μm 2 lesion in cASO-treated OB mice compared to 38589 ± 9507 μm 2 in APOC3 ASO-treated OB mice, p<0.05, n=12-15). The reduction in lesion size with APOC3 treatment was associated with fewer macrophages and reduced perilipin 2 staining (a marker for lipid droplet formation). In the kidney, diabetes resulted in a dramatic increase in glomerular hypertrophy, neutral lipid accumulation, APOC3, and APOE-accumulation, which APOC3 ASO-treatment attenuated. Furthermore, diabetes resulted in monocyte recruitment, macrophage accumulation, and macrophage lipid loading in the glomeruli, all of which was dramatically suppressed in the setting of APOC3 silencing (36% of glomerular macrophages were lipid loaded in OB cASO mice whereas only 9% were lipid loaded in APOC3-ASO treated mice, p<0.0001). The recruitment was driven by increased endothelial cell ICAM1 expression, but monocyte lipid loading may also contribute. Intriguingly, APOC3-ASO treatment reduced diabetes-associated urinary albumin creatinine ratio but did not affect it in non-diabetic mice (WT mice: 374 ± 71 μg albumin/mg creatinine, OB cASO mice: 4648 ± 1021 μg/mg and OB mice with APOC3 ASO: 2341 ± 439 μg/mg, p<0.05, n=12-14). Together, this suggests that targeting APOC3 and diabetic dyslipidemia might be beneficial for both diabetes-accelerated atherosclerosis and kidney disease.