Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While the progression of primary glomerular disease to induce tubulointerstitial lesions is well established, the effect of tubular injury to trigger glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we utilized conditional knockout mice with tubule-specific ablation of β-catenin (Ksp-β-cat-/-), and subjected them to chronic angiotensin II (Ang II) infusion or adriamycin. Compared to control mice, Ksp-β-cat-/- mice were dramatically protected from proteinuria and glomerular damage. Matrix metalloproteinase-7 (MMP-7), a downstream target of β-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-β-cat-/- littermates. Incubation of isolated glomeruli with MMP-7 ex vivo led to nephrin depletion and impaired glomerular permeability. Furthermore, MMP-7 specifically and directly degraded nephrin in cultured glomeruli or cell-free systems, and this effect was dependent on its proteolytic activity. In vivo, expression or infusion of exogenous MMP-7 caused proteinuria, and genetic ablation of MMP-7 protected mice from Ang II-induced proteinuria and glomerular injury. Collectively, these results demonstrate that beta-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.
Roderick J. Tan, Yingjian Li, Brittney M. Rush, Débora Malta Cerqueira, Dong Zhou, Haiyan Fu, Jacqueline Ho, Donna Beer Stolz, Youhua Liu
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