Long Luosha, Li Meng, Wang Minghui, Liang Baien, Huang Meiying, Yuan Xi, Wu Xinyan, Guo Xiangdong, Li Suchun, Liu Zhende, Liu Weizhi, Chen Wei, Wang Weidong, Lyu Qianqian, Li Chunling
Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pathology and Pathophysiology, Pu Ai Medical School, Shaoyang University, Shaoyang, China.
Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Life Sci. 2025 Jun 15;371:123593. doi: 10.1016/j.lfs.2025.123593. Epub 2025 Mar 29.
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.
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.
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.
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.
细胞外基质（ECM）过度沉积是肾纤维化的特征，这是由于合成与降解之间的失衡所致。纤连蛋白可调节其他ECM的沉积，因此在肾纤维化进展中起关键作用。甘露糖受体C型1（MRC1）主要在巨噬细胞上表达，拥有一个细胞外II型纤连蛋白结构域，可结合并内化胶原蛋白，从而参与纤维化调节。本研究的目的是探讨MRC1是否参与纤连蛋白的内化，以及海藻酸盐的降解产物海藻寡糖（AOSC）是否通过MRC1对肾纤维化的消退具有有益作用。
在MRC1野生型（MRC1-WT）和MRC1基因敲除型（MRC1-KO）小鼠中，通过单侧输尿管梗阻（UUO）和单侧缺血再灌注损伤（UIRI）构建肾纤维化模型。用转化生长因子-β1（TGF-β1）处理RAW264.7细胞以诱导促纤维化反应。检测纤维化标志物的表达和纤连蛋白的内吞作用。
MRC1基因敲除加重了UUO和UIRI模型中的肾纤维化。抑制MRC1会加剧TGF-β1诱导的RAW264.7细胞中的促纤维化反应。MRC1通过Arp2/3-Kindlin-2信号通路调节整合素β1介导的纤连蛋白内吞作用。AOSC通过增加MRC1表达和纤连蛋白的内吞作用改善肾纤维化。
我们的研究结果突出了MRC1和纤连蛋白内吞作用在肾纤维化发展中的重要性，表明AOSC激活MRC1可能是延缓肾纤维化进展的一种治疗选择。
