TLR4 Inhibition Attenuates Vascular Remodeling in A Mouse Model of Chronic Kidney Disease.

Abstract

AIM: Chronic kidney disease (CKD) is linked to accelerated vascular remodeling, characterized by medial thickening and fibrosis; however, the molecular mechanisms driving this process remain unclear. METHODS: We investigated the role of toll-like receptor 4 (TLR4) in CKD-associated vascular remodeling using a 5/6 nephrectomy mouse model. TLR4 signaling was selectively inhibited by the long-term administration of TAK-242, a small-molecule-specific inhibitor of TLR4. RESULTS: TLR4 blockade decreased aortic medial thickening and perivascular fibrosis independent of blood pressure. Immunostaining revealed that blockade of TLR4 decreased Mac-3-positive macrophage accumulation and Ki-67-positive proliferating cells in the aorta. The mRNA expression of IL-6 was suppressed in aortas treated with TAK-242. Disulfide HMGB1 induced the expression of IL-6 in macrophages. Serum from CKD mice induced the expression of IL-6 in RAW264.7 cells and promoted in vitro vascular smooth muscle cell growth, both of which were attenuated with serum from TAK-242-treated CKD mice. CONCLUSION: These findings suggest that TLR4-mediated sterile inflammation may contribute to vascular remodeling in CKD and that modulation of TLR4 signaling could be explored as a potential therapeutic strategy to mitigate cardiovascular complications in CKD patients.