Identification of matrix metalloproteinase-10 as a key mediator of podocyte injury and proteinuria

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.