Activation of mannose receptor C type 1 in macrophages improves renal fibrosis through mediating fibronectin endocytosis

Aims

Excess extracellular matrix (ECM) deposition is the characteristic of renal fibrosis, owing to the imbalance between synthesis and degradation. Fibronectin could regulate the deposition of other ECM, thus plays a crucial role in the progression of renal fibrosis. Mannose receptor C type 1 (MRC1), largely expressed on macrophages, owns an extracellular fibronectin type II domain that binds to and internalizes collagen and thus involves in fibrosis modulation. The purpose of the present study was to investigate whether MRC1 participates in the internalization of fibronectin and whether alginate oligosaccharides (AOSC), a degradation product of alginate, has beneficial effects in the resolution of renal fibrosis via MRC1.

Materials and methods

Renal fibrosis models were constructed by unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) in MRC1-WT and MRC1-KO mice. RAW264.7 cells were treated with TGF-β1 to induce pro-fibrotic responses. Expression of fibrotic markers and fibronectin endocytosis were examined.

Key findings

MRC1 gene knockout aggravated renal fibrosis in UUO and UIRI models. Inhibition of MRC1 exacerbated TGF-β1-induced pro-fibrotic responses in RAW264.7 cells. MRC1 regulated integrin β1-mediated fibronectin endocytosis through Arp2/3-Kindlin-2 signaling pathway. AOSC improved renal fibrosis by increasing MRC1 expression and endocytosis of fibronectin.

Significance

Our findings highlight the importance of MRC1 and fibronectin endocytosis in the development of renal fibrosis, suggesting that activation of MRC1 by AOSC is probably a therapeutic option to delay the progress of kidney fibrosis.