ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/jci.insight.177268
1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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1Division of Metabolism, Endocrinology, and Nutrition, UW Medicine Diabetes, University of Washington, Seattle, United States of America
2Phoenix VA Health Care System, Phoenix, United States of America
3Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America
4Ionis Pharmaceuticals, Carlsbad, United States of America
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Published May 14, 2024 - More info
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 key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial (VADT). Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated BTBR wildtype (WT) and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO (cASO), all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.