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Abstract: PO0948

Apolipoprotein C3 Inhibition Reduces Diabetic Kidney Disease and Atherosclerosis in a Mouse Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hsu, Cheng-Chieh, University of Washington School of Medicine, Seattle, Washington, United States
  • Kramer, Farah, University of Washington School of Medicine, Seattle, Washington, United States
  • Alpers, Charles E., University of Washington School of Medicine, Seattle, Washington, United States
  • Crooke, Rosanne M., Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Kanter, Jenny E., University of Washington School of Medicine, Seattle, Washington, United States
Background

Diabetes increases the risk of cardiovascular disease and kidney disease. Importantly, the majority of the excess cardiovascular risk in people with diabetes is observed in those who also have kidney disease. Apolipoprotein C3 (APOC3) is a small lipoprotein that is elevated by insulin-insufficiency and regulates plasma triglyceride levels.

Methods

To test if APOC3, and the dyslipidemia it represents, play a role in diabetic kidney disease (DKD) 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 LDLR ASO).

Results

APOC3 ASO treatment reduced triglycerides, triglyceride-rich lipoproteins, and prevented diabetes-accelerated atherosclerosis in the brachiocephalic artery and the aorta (aortic lesion was 9.3 ± 1.5 mm2 lesion in cASO-treated OB mice compared to 4.7 ± 0.93 mm2 in APOC3 ASO-treated OB mice, p<0.001, n=7-10). Intriguingly, APOC3-ASO treatment reduced diabetes-associated urinary albumin excretion but had no effect on non-diabetic mice (WT mice: 108 ± 24.0 mg urinary albumin/day, OB cASO mice: 1076 ± 219 mg/day and OB mice with APOC3 ASO: 435 ± 63 mg/day, p<0.001, n=7-14). Diabetes resulted in a dramatic increase in glomerular neutral lipid and APOC3-accumulation, which was attenuated by APOC3 ASO-treatment. Diabetes led to a doubling of glomerular volume (45126 ± 1908 μm3 glomerular volume in OB mice vs. 21775 ± 1041μm3 in WT mice, p<0.001, n=7-14), increased glomerular PAS-staining indicative of mesangial expansion (2494 ± 332 μm2 PAS-positive matrix in OB mice and 822 ± 40 μm2 in WT mice, p<0.001; or from 21% in WT to 28% in diabetes, p<0.01), and a significant loss of podocytes (80 ± 8 podocytes/106 μm3 glomerular volume in OB mice and 230 podocytes/106 μm3 glomerular volume in WT mice, p<0.001), all of which were in part reversed by APOC3 inhibition (glomerular volume in OB mice treated with APOC3 ASO 36331 ± 2240 μm3, p<0.05; PAS area 1761 ± 131 μm2, p<0.01; and podocyte density 114 ± 9 podocytes/106 μm3 glomerular volume, p=0.07, all compared to OB mice treated with cASO).

Conclusion

Together, this suggests that targeting APOC3 and diabetic dyslipidemia might be beneficial for both diabetes-accelerated atherosclerosis and DKD.

Funding

  • NIDDK Support