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

Roderick J Tan1, Yingjian Li2, Brittney M Rush1

  • 1Renal-Electrolyte Division, Department of Medicine.

JCI Insight
|November 20, 2019
PubMed

Insights

Injured kidney tubules release MMP-7, which degrades nephrin, causing proteinuric chronic kidney disease (CKD). Blocking this pathway protects against glomerular damage and kidney disease progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Proteinuric chronic kidney disease (CKD) is a global health issue.
  • The link between tubular injury and glomerular damage in CKD is not fully understood.
  • Tubular injury is known to induce tubulointerstitial lesions, but the reverse is less clear.

Purpose of the Study:

  • To investigate the role of injured tubules in causing glomerular damage.
  • To test the hypothesis that injured tubules secrete mediators that harm glomerular health.
  • To elucidate the molecular mechanism by which tubular injury contributes to proteinuria.

Main Methods:

  • Utilized conditional knockout mice with tubule-specific ablation of β-catenin (Ksp-β-cat-/-).
  • Administered chronic angiotensin II (Ang II) infusion or Adriamycin to mice.
  • Assessed proteinuria, glomerular damage, and nephrin levels.
  • Investigated the role of Matrix Metalloproteinase-7 (MMP-7) in vitro and in vivo.
  • Performed ex vivo incubation of isolated glomeruli with MMP-7 and cell-free degradation assays.

Main Results:

  • Ksp-β-cat-/- mice showed significant protection from proteinuria and glomerular damage compared to controls.
  • β-catenin-driven upregulation of MMP-7 in tubules was crucial for Ang II-induced kidney injury.
  • MMP-7 directly degraded nephrin, a key slit diaphragm protein, leading to impaired glomerular permeability.
  • Exogenous MMP-7 administration induced proteinuria, while MMP-7 genetic ablation protected against kidney injury.

Conclusions:

  • Tubular β-catenin signaling drives MMP-7 release, promoting glomerular injury.
  • MMP-7 directly degrades nephrin, causing proteinuria and exacerbating CKD.
  • Targeting the β-catenin-MMP-7-nephrin axis may offer a therapeutic strategy for proteinuric CKD.
Keywords:
Chronic kidney diseaseMouse modelsNephrologyProteases

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