Moderate kidney disease inhibits atherosclerosis regression

Abstract

Chronic kidney disease (CKD) accelerates cardiovascular disease. The mechanisms that explain this independent, excess risk associated with CKD have not been fully elucidated.

Objectives: We propose that impaired regression of atherosclerosis in renal disease represents a novel risk factor for the heightened morbidity and mortality and resistance to treatment observed in patients with CKD.

Methods and results: Using a transplant model to study atherosclerosis regression, we transplanted atheromatous aortic segments generated in Apolipoprotein E knock-out (ApoE(-/-)) mice, into either control or moderately uremic, normolipidemic, wild-type mice. In non-uremic mice, lesions regressed 55%, whereas lesions in uremic mice increased in size by 17% (p<0.01 for control vs. uremic). The lesions in uremic mice were also characterized by a greater presence of macrophages (36,300 microm(2) vs. 12,600 microm(2), p<0.01). This finding was despite upregulation of chemokine receptor 7 (CCR7), normally a migration factor, in uremic lesion macrophages. Gene expression analysis of lesion macrophages showed relative down-regulation of serum response factor (SRF) target genes in the uremic group, consistent with impaired CCR7 signaling.

Conclusion: Moderate kidney disease inhibits regression of atherosclerosis in a mouse transplant model. This inhibition may be a result of impaired CCR7 signaling.

Figure 1

(A) Average atherosclerosis lesion area from baseline ApoE ^−/− controls (left), wildtype control recipients (center) and wildtype uremic recipients (right). As expected, non-uremic mice showed significant regression of atherosclerotic lesions after 5 days. Uremic mice showed no regression in the same time frame. (B) Representative cross-sections stained with anti-CD68. Bar = 200μm.

Figure 2

Macrophage Content as determined by average CD68 positivity of aortic-cross sections from baseline ApoE ^−/− controls (left), wildtype control recipients (center) and wildtype uremic recipients (right). At baseline, atherosclerotic plaques were highly enriched with CD68⁺ macrophages. After 5 days in a non-uremic wildtype environment, there was significant depletion of these cells. A trend toward fewer lesion macrophages was seen in the uremic group, though these mice still had significantly more macrophages after 5 days than in the control group.

Figure 3

(A) Aortic cross-sections of intra-plaque staining of CCL19 (top row) or CCL21 (bottom row) from aortic-cross sections of baseline controls (left), normal control recipients (center) and uremic recipients (right). Both ligands showed equivalent staining in all 3 groups; (B) serial sections stained for CD68 (top row) and CCR7 (bottom row) under baseline (left), normal control (center) and uremic (right) conditions. CCR7 was much more highly expressed in uremic lesions than in controls or at baseline. CCR7 staining co-localized with CD68+ areas of the plaques.