Zuo Yangyang, Wang Cong, Sun Xiaoli, Hu Chengxiao, Liu Jixing, Hong Xue, Shen Weiwei, Nie Jing, Hou Fan Fan, Zhou Lili, Liu Youhua
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
Kidney Int. 2021 Oct;100(4):837-849. doi: 10.1016/j.kint.2021.05.035. Epub 2021 Jun 24.
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.
足细胞损伤或功能障碍在慢性肾脏病导致蛋白尿和肾小球硬化过程中起关键作用。为寻找参与足细胞损伤的新因子，我们通过RNA测序对肾小球进行基因表达谱分析。这种无偏倚的方法使我们发现基质金属蛋白酶10（MMP - 10），一种分泌型锌依赖性内肽酶，是肾小球损伤后上调最明显的基因之一。在动物模型和蛋白尿性慢性肾脏病患者中，MMP - 10在受损肾小球的足细胞中特异性上调。慢性肾脏病患者循环中MMP - 10水平也升高，且与肾功能不全的严重程度相关。在足细胞特异性表达MMP - 10的转基因小鼠中，阿霉素诱导损伤后蛋白尿加重。同时伴有更严重的足细胞病变和肾小球硬化性病变。相反，体内敲低MMP - 10可使小鼠免受蛋白尿影响，恢复足细胞完整性并减少肾纤维化。有趣的是，MMP - 10降低足细胞紧密连接蛋白闭合蛋白1（ZO - 1）水平，但不影响其mRNA水平。在体外将纯化的ZO - 1与MMP - 10孵育直接导致其蛋白水解降解，提示ZO - 1是MMP - 10的新底物。因此，我们的研究结果表明，MMP - 10的诱导可通过降解ZO - 1导致足细胞损伤，从而促进慢性肾脏病中的蛋白尿和肾小球硬化。
