Dataset Information


Tubular injury triggers podocyte dysfunction by ?-catenin-driven release of MMP-7.

ABSTRACT: Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we used conditional knockout mice with tubule-specific ablation of ?-catenin (Ksp-?-cat-/-) and subjected them to chronic angiotensin II (Ang II) infusion or Adriamycin. Compared with control mice, Ksp-?-cat-/- mice were dramatically protected from proteinuria and glomerular damage. MMP-7, a downstream target of ?-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-?-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 ?-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.

PROVIDER: S-EPMC6975262 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

2011-01-01 | S-EPMC4300105 | BioStudies
| S-EPMC5177899 | BioStudies
| S-EPMC3328599 | BioStudies
| S-EPMC3518538 | BioStudies
2017-01-01 | S-EPMC5543238 | BioStudies
| S-EPMC2736766 | BioStudies
| S-EPMC22170 | BioStudies
| S-EPMC2739711 | BioStudies
| S-EPMC8692909 | BioStudies
| S-EPMC4112437 | BioStudies