Matrix metalloproteinase 12 modulates high-fat-diet induced glomerular fibrogenesis and inflammation in a mouse model of obesity.
Matrix metalloproteinase 12 modulates high-fat-diet induced glomerular fibrogenesis and inflammation in a mouse model of obesity.
复制标题
基质金属蛋白酶 12 在肥胖小鼠模型中调节高脂肪饮食诱导的肾小球纤维化和炎症。
DOI：
10.1038/srep20171
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发表时间：
2016-01-29
影响因子：
4.6
通讯作者：
Nie L
中科院分区：
文献类型：
--
作者：
Niu H;Li Y;Li H;Chi Y;Zhuang M;Zhang T;Liu M;Nie L
肥胖引起的肾损伤导致蛋白尿，其特征在于肾功能进行性下降，导致肾小球硬化和肾纤维化。基质金属蛋白酶（MMPs）通过降解多种细胞外基质和调节效应蛋白的活性来调节炎症和纤维化。MMP-12表达的异常调节与腹主动脉瘤、动脉粥样硬化和肺气肿有关，但其潜在机制尚不清楚。本研究使用apo E−/−或apo E−/−MMP-12−/−小鼠检测MMP-12在肾小球纤维化和炎症中的功能，并维持高脂饮食（HFD）3，6或9个月。MMP-12缺失可减少肾小球基质的积聚，下调NADPH氧化酶4和亚单位p67 phox的表达，表明肾脏氧化应激受到抑制。此外，在喂食HFD的apo E−/−MMP-12−/−小鼠的肾小球中，炎症相关分子MCP-1和巨噬细胞标志物-CD 11b的表达降低。MMP-12的巨噬细胞浸润到肾小球有助于IV型胶原和纤维连接蛋白的降解。由于Bowman间隙中的肾氧化应激而形成新月体是纤维化和炎症发展的主要因素。这些结果表明，调节MMP-12活性可能是治疗新月体肾小球肾炎和纤维化的治疗策略。
Obesity-induced kidney injury contributes to albuminuria, which is characterized by a progressive decline in renal function leading to glomerulosclerosis and renal fibrosis. Matrix metalloproteinases (MMPs) modulate inflammation and fibrosis by degrading a variety of extracellular matrix and regulating the activities of effector proteins. Abnormal regulation of MMP-12 expression has been implicated in abdominal aortic aneurysm, atherosclerosis, and emphysema, but the underlying mechanisms remain unclear. The present study examined the function of MMP-12 in glomerular fibrogenesis and inflammation using apo E−/− or apo E−/−MMP-12−/− mice and maintained on a high-fat-diet (HFD) for 3, 6, or 9 months. MMP-12 deletion reduced glomerular matrix accumulation, and downregulated the expression of NADPH oxidase 4 and the subunit-p67phox, indicating the inhibition of renal oxidative stress. In addition, the expression of the inflammation-associated molecule MCP-1 and macrophage marker-CD11b was decreased in glomeruli of apo E−/−MMP-12−/− mice fed HFD. MMP-12 produced by macrophages infiltrating into glomeruli contributed to the degradation of collagen type IV and fibronectin. Crescent formation due to renal oxidative stress in Bowman’s space was a major factor in the development of fibrogenesis and inflammation. These results suggest that regulating MMP-12 activity could be a therapeutic strategy for the treatment of crescentic glomerulonephritis and fibrogenesis.