Abstract 1203: Mild Renal Dysfunction Caused by Uninephrectomy Accelerated the Development of Atherosclerosis by Augmented Monocyte Mobilization from Bone Marrow via CCR2-Mediated Signals
[BACKGROUND] Chronic kidney disease (CKD) is now recognized to be an independent risk factor for cardiovascular disease (CVD). However, the underling mechanism for CKD-associated proatherogenic actions remains poorly defined.
[METHOD AND RESULT] Male apoE deficient mice underwent uninephrectomy (UNX: n=12) or sham operation (sham: n=12) and were bred on western diet at 8 wks of age. 4 and 8 weeks after UNX or sham, atherosclerotic lesion area in aortic root was evaluated. UNX mice showed significant exaggeration of atherosclerotic lesion area compared with sham mice (1.5 ± 0.3 vs. 0.9 ± 0.1 mm2: 4wks after UNX, P<0.05, 4.4 ± 0.3 vs. 2.6 ± 0.5 mm2: 8wks after UNX, P=0.02). The accumulation of monocyte/macrophages in UNX mice was also augmented by 83% 8wks after UNX (P=0.02), suggesting that monocyte migration into the atherosclerotic lesions was much exaggerated in UNX mice compared with sham mice. Consistent with this finding, the numbers of circulating Ly-6Chi and CCR2+ monocytes, preferentially accumulating into the inflammatory tissues, remarkably reduced in 8 wks than those in 4 wks after UNX in both the two groups; however, the percent decrease in the numbers of circulating monocytes appeared to be lower in UNX mice than sham mice (63 vs. 78 % and 63 vs. 80 %, UNX vs. sham mice, Ly-6Chi and CCR2+ monocyte, respectively). To investigate whether monocyte mobilization from the bone marrow was augmented in UNX mice, we next examined the expression of CCR2 in bone marrow monocyte, which was closely implicated in the mobilization of monocyte from bone marrow into the circulation. The frequencies of CCR2+ CD11bhiGr-1− monocyte in bone marrow were markedly augmented by 96 % (P<0.001) in UNX mice 4 wks after UNX compared with sham mice.
[CONCLUSION] Mild renal dysfunction caused by UNX accelerated the development of atherosclerosis, in which monocyte mobilization from bone marrow was augmented accompanied by the elevated frequencies of bone marrow CCR2+ monocyte, suggesting that bone marrow CCR2-mediated signals could be a promising therapeutic target for the prevention of CVD in patients with CKD.