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基质金属蛋白酶 12 调节肥胖小鼠模型中高脂肪饮食诱导的肾小球纤维化和炎症。

Matrix metalloproteinase 12 modulates high-fat-diet induced glomerular fibrogenesis and inflammation in a mouse model of obesity.

机构信息

Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.

Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.

出版信息

Sci Rep. 2016 Jan 29;6:20171. doi: 10.1038/srep20171.

DOI:10.1038/srep20171
PMID:26822129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4731752/
Abstract

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-p67(phox), 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.

摘要

肥胖引起的肾脏损伤导致白蛋白尿，其特征是肾功能逐渐下降，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，但潜在机制尚不清楚。本研究使用载脂蛋白 E（-/-）或载脂蛋白 E（-/-）MMP-12（-/-）小鼠和高脂肪饮食（HFD）饲养 3、6 或 9 个月，研究了 MMP-12 在肾小球纤维化和炎症中的作用。MMP-12 缺失减少了肾小球基质的积累，并下调了 NADPH 氧化酶 4 和亚基-p67（phox）的表达，表明抑制了肾脏氧化应激。此外，在高脂肪饮食喂养的载脂蛋白 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-CD11b 的表达减少。浸润到肾小球中的巨噬细胞产生的 MMP-12 有助于胶原 IV 型和纤维连接蛋白的降解。Bowman 空间中由于肾氧化应激而形成的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一种治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/98da16e8522c/srep20171-f9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/bee2a22e9ea1/srep20171-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/da472c515840/srep20171-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/4c9a4d9ec03c/srep20171-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/98da16e8522c/srep20171-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/77a356069efc/srep20171-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/86d8d33e0558/srep20171-f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/31a5c33a3b99/srep20171-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/26ecb27d3de7/srep20171-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/bee2a22e9ea1/srep20171-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/da472c515840/srep20171-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/4c9a4d9ec03c/srep20171-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a5b/4731752/98da16e8522c/srep20171-f9.jpg

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