APOC-III mediated dyslipidemia in diabetic kidney disease and atherosclerosis
People with diabetes are more likely to have both microvascular and macrovascular complications, such as diabetic kidney disease (DKD) and of cardiovascular disease (CVD). Diabetic dyslipidemia, characterized by increased triglycerides and reduced HDL cholesterol, in a known risk factor for CVD, but also an independent risk factor for progression of DKD. New data indicate that APOC-III plays a critical role this diabetic dyslipidemia. Preliminary data suggests that apolipoprotein C-III (APOC-III) is elevated in the setting of DKD and that blocking APOC-III reduces DKD and atherosclerosis in mouse models. The role of APOC-III in DKD and atherosclerosis will be addressed in the aim: Does blocking diabetes-induced APOC-III prevent diabetic dyslipidemia, kidney disease and atherosclerosis in a novel mouse model of combined diabetic kidney disease and atherosclerosis, via a pathway that involves FOXK1-dependent CCL2 production? The hypothesis is that that APOC-III accelerates DKD and diabetes-accelerated atherosclerosis through a process that involves diabetic dyslipidemia and associates with excessive accumulation and activation of macrophages in the glomerulus and artery wall via a pathway that involves lipid-induced activation of the mTORC1-FOXK1-CCL2 pathway. This hypothesis will be tested using an APOC-III ASO generated by Ionis Pharmaceuticals in a mouse model of T2D, with or without targeted suppression of FOXK1 in macrophages. A human ASO has already been tested in T2 diabetic patients with promising lipid-lowering results, but the effect on atherosclerosis and kidney disease are still unknown, thus these might have strong translational impacts, and may open up avenues for new, improved therapies.

Curation Flag Information