Increased Atherosclerotic Lesion Formation and Vascular Leukocyte Accumulation in Renal Impairment are Mediated by Interleukin 17A
Rationale: Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood.
Objective: This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes.
Methods and Results: Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in two murine atherosclerosis models, Apolipoprotein E (Apoe-/-) and LDL receptor (LDLr-/-) deficient mice. The number of aortic myeloid cells increased significantly. They took up less oxidized LDL, while CD11c expression, interaction with T cells and aortic T cell proliferation were significantly enhanced in renal impairment. In human PBMC cultures, chronic kidney disease serum decreased lipid uptake and increased HLAII expression. Supplementation with Interleukin (IL)-17A similarly increased HLAII and CD11c expression and impaired oxLDL uptake. IL-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of IL-17A in LDLr-/- mice by lethal irradiation and reconstitution with Il17a-/- bone marrow abolished the effect of renal impairment on aortic CD11b+ myeloid cell accumulation, CD11c expression and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function.
Conclusions: Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for IL-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.
- Received June 2, 2013.
- Revision received July 31, 2013.
- Accepted August 1, 2013.