Myeloid RANK Deletion Accelerate the Development of Atherosclerosis in ApoE Deficient Mice with Chronic Kidney Disease

Objective: Chronic kidney disease (CKD) greatly increases the risk of cardiovascular disease morbidity and mortality. Mounting data has identified the receptor activator of NF-κB (RANK) pathway as an important mediator of the accelerated atherosclerosis and vascular calcification observed in CKD. Here we investigated the role of myeloid RANK in a model of CKD accelerated atherosclerosis and vascular calcification in apolipoprotein E-deficient mice (apoE -/- ). Methods and Results: We used the Lys M promoter to conditionally delete granulocyte and monocyte RANK in atherogenic apoE -/- mice. To induce CKD RANK (flox/flox) LysM (cre/+) Apoe (-/-) (apoE ΔRANK ) and LysM (cre/+) Apoe (-/-) (apoE CTL ) underwent a two-step surgical procedure to achieve 5/6 th nephrectomy. Additional control animals underwent sham surgeries. Blood urea nitrogen (BUN) levels were elevated approximately two-fold in the CKD mice relative to sham-operated mice regardless of genotype. CKD was accompanied by a trend toward lower body weight, as well as slightly elevated circulating phosphate levels at the time of sacrifice. CKD induced a 47% elevation of plasma cholesterol levels in the apoE ΔRANK and apoE CTL mice, with no significant difference in cholesterol levels between the apoE ΔRANK and apoE CTL CKD mice. Interestingly, CKD resulted in elevated triglycerides in apoE ΔRANK mice, but not in apoE CTL mice. CKD mice age 22 and 34 weeks had larger average lesional cross-section areas in the root of the aorta as compared to sham operated mice (p ΔRANK mice were significantly larger than those from apoE CTL CKD mice. In all genotypes and disease conditions we observed very little vascular calcification. Conclusions: These results suggest an atheroprotective role for myeloid RANK signaling in CDK-dependent lesion acceleration.