Abstract 340: Phenotypic Conversion of Perivascular Adipose Tissue in Uninephrectomized Apoe-Deficient Mice: Possible Role in the Early Stage of Atherosclerosis in Chronic Kidney Disease

Abstract

BACKGROUND: Chronic kidney disease (CKD) is now recognized to be an independent risk factor for cardiovascular disease. Recently, perivascular adipose tissue (PVAT) has been shown to play a crucial role in the pathogenesis of atherosclerosis; however, the role of PVAT in the CKD-associated proatherogenic actions remains undefined.

METHOD AND RESULT: Eight-week-old apoE deficient mice underwent uninephrectomy (UNX) or sham operation and were fed a western diet starting at 12 wks of age. UNX mice at the age of 20 wks showed a significant exaggeration of atherosclerotic lesion area (53%, P<0.05). Hemodynamic data, lipid profile, and plasma creatinine concentrations did not differ between the two groups. To elucidate the underlying mechanisms of minor renal insufficiency-induced atherosclerosis, we first examined the number of circulating inflammatory monocytes and the mRNA expression levels of VCAM-1 and ICAM-1 in the vasculature at 16 wks of age. However, there was no difference between the two groups, suggesting that uninephrectomy did not effect on either western diet-induced mobilization of bone marrow-derived monocytes or endothelial activation in the early stage of atherosclerosis. We therefore focused on the PVAT surrounding the thoracic aorta, which showed multilocular fat droplet and high expression levels of brown adipocyte-specific genes. The fat pad weight and cross-sectional area of PVAT including the infiltration of CD45+ cells did not differ between the two groups. While mRNA expression levels of adipocyte differentiation marker genes (PPARγ, FABP4, and adiponectin) were equivalent between the two groups, brown adipocyte-specific marker genes (UCP-1, Elovl3) showed a significantly lower expression in UNX mice (P<0.01). In contrast, white adipocyte-specific marker gene Tcf21 was markedly up-regulated (101%, P<0.05), accompanied by the increased expression of angiotensinogen gene (85%, P<0.05). The concentration of serum angiotensin II did not differ between the two groups.

CONCLUSION: Phenotypic conversion of perivascular brown to white adipose tissue along with the depot-specific local activation of renin-angiotensin system is a possible mechanism underlying the early stage of atherosclerosis in CKD.