The Link Between Diabetic Dyslipidemia and Macrophages in Diabetic Kidney Disease and Diabetes-accelerated Atherosclerosis

Abstract

Diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease. Macrophages and lipid-loaded macrophages (foam cells) accumulate in the kidney at all stages of diabetic kidney disease (DKD). Lowering levels of circulating triglyceride-rich lipoproteins (TRLs) reduced the accumulation of these foamy macrophages, suggesting that macrophages are responsive to the metabolic challenges in diabetes. Monocytes, the circulating precursors of macrophages, are similarly reprogrammed by diabetes and altered TRL levels, becoming lipid-loaded in the circulation, which promotes their priming and trafficking to the kidney. Single-cell RNA sequencing indicated that TRLs reprogram renal macrophages to enhance macrophage lipid handling and efferocytosis, while flow cytometry identifies the CD36 receptor as a key regulator in foam cell accumulation. Whether these lipid-loaded macrophages contribute to DKD progression was unknown. To address this question, we generated mice with hematopoietic CD36 deficiency, which impaired the accumulation of lipid-loaded macrophages in the diabetic kidney. This resulted in worsening of diabetes-induced albuminuria and diabetes-accelerated atherosclerosis, associated with increased lipid accumulation in non-macrophages. Together, these findings support a role for lipid-loaded macrophages in maintaining tissue lipid homeostasis in the kidney and artery wall and thereby shaping disease initiation and progression by protecting local cells from lipid toxicity.