足细胞
肾小球硬化
蛋白尿
基因敲除
急性肾损伤
下调和上调
医学
内科学
局灶节段性肾小球硬化
生物
肾
内分泌学
肾脏疾病
生物化学
基因
细胞凋亡
作者
Yangyang Zuo,Cong Wang,Xiaoli Sun,Chengxiao Hu,Jixing Liu,Hong Xue,Weiwei Sui,Jing Nie,Fan Fan Hou,Lili Zhou,Youhua Liu
标识
DOI:10.1016/j.kint.2021.05.035
摘要
Podocyte injury or dysfunction plays an essential role in causing proteinuria and glomerulosclerosis in chronic kidney diseases. To search for new players involved in podocyte injury, we performed gene expression profiling in the glomeruli by RNA sequencing. This unbiased approach led us to discover matrix metalloproteinase-10 (MMP-10), a secreted zinc-dependent endopeptidase, as one of the most upregulated genes after glomerular injury. In animal models and patients with proteinuric chronic kidney diseases, MMP-10 was upregulated specifically in the podocytes of injured glomeruli. Patients with chronic kidney diseases also had elevated circulating levels of MMP-10, which correlated with the severity of kidney insufficiency. In transgenic mice with podocyte-specific expression of MMP-10, proteinuria was aggravated after injury induced by Adriamycin. This was accompanied by more severe podocytopathy and glomerulosclerotic lesions. In contrast, knockdown of MMP-10 in vivo protected mice from proteinuria, restored podocyte integrity and reduced kidney fibrosis. Interestingly, MMP-10 reduced podocyte tight junctional protein zonula occludens-1 (ZO-1) but did not affect its mRNA level. Incubation of purified ZO-1 with MMP-10 directly resulted in its proteolytic degradation in vitro, suggesting ZO-1 as a novel substrate of MMP-10. Thus, our findings illustrate that induction of MMP-10 could lead to podocyte injury by degrading ZO-1, thereby promoting proteinuria and glomerulosclerosis in chronic kidney diseases.
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