Abstract We0055: Lipid-loaded Myeloid Cells Accumulate in Atherosclerotic Lesions and Kidneys in a Mouse Model of Cardiovascular-Kidney-Metabolic Syndrome: Lack of Protective Effects of Hematopoietic CD36-Deficiency

Diabetes accentuates the risk of atherosclerotic cardiovascular disease (CVD), which is further magnified in individuals with concurrent impaired kidney function. The interplay between metabolic dysfunction and its complications is now recognized as the cardiovascular-kidney-metabolic (CKM) syndrome. Lipid-laden macrophages are a hallmark of atherosclerosis. Our studies show that lipid-laden macrophages also accumulate in glomeruli in a new model that mimics type 2 diabetes (T2D) and develops human-like diabetic kidney disease (DKD) and atherosclerosis, contributing to CKM syndrome. Transcriptomic analysis suggests that lipid-responsive pathways are among the most enriched pathways in macrophages in both human and mouse renal macrophages (e.g., lipoprotein catabolic process: NES 1.9, padj (FDR)=3x10 -4 human, NES 1.8, padj=2x10 -3 mouse). Furthermore, we show that circulating monocytes become lipid-loaded in diabetes (4-fold, p=1x10 -4 , N=6-8) via a process that, at least in vitro , depends on class B scavenger receptor CD36. We aimed to test the role of CD36 in monocyte and macrophage lipid loading and whether CD36 contributes to DKD and atherosclerosis in CKM. To perform these studies, we transplanted non-diabetic (ND) and T2D mice with wild-type or CD36 -/- bone marrow. All mice were LDL receptor-deficient and fed a low-fat semipurified diet for 12 weeks. While hematopoietic CD36-deficiency abolished monocyte CD36 levels, it did not protect from diabetes-augmented atherosclerosis in the aortic sinus (983 ± 645 [mean ± SEM] μm 2 in ND WT vs. 32671 ± 11302 in T2D WT, 5x10 -3 , and 31739± 9680 in T2D CD36 -/- , p=5x10 -3 , N=5-11), nor did it prevent the development of diabetes-induced albuminuria. Moreover, after 12 weeks, hematopoietic CD36-deficiency resulted in an augmentation of diabetes-induced albuminuria (124. 3 ± 15.1 μg/24 hours in T2D WT, and 406 ± 99 in T2D CD36 -/- , p=1.6x10 -3 , N=11-13). In conclusion, these studies suggest that macrophage lipid loading may be protective rather than deleterious in kidney complications in CKM syndrome.