Combined application of rapamycin and atorvastatin improves lipid metabolism in apolipoprotein E-deficient mice with chronic kidney disease

Abstract

Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE(-/-)) mice. Oil Red O staining revealed that treatment with RAPA and RAPA+ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXR alpha, CYP7A1, ABCG1, PPAR gamma, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosis-promoting cytokines in the spleen (Tnf-alpha, Il-6 and Il-1 beta) and aorta (Tnf-alpha and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA+ATV decreased the levels of Tnf-alpha and Il-1 beta in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE(-/-) mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism.