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Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis

Dong Zhou1, Haiyan Fu2, Lu Zhang3

  • 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Journal of the American Society of Nephrology : JASN
|March 25, 2017
PubMed

Insights

Tubule-derived Wnt ligands are crucial drivers of kidney fibrosis in chronic kidney disease (CKD). Blocking Wnt secretion from kidney tubules reduces fibrosis by inhibiting myofibroblast activation and preserving tubular integrity.

Area of Science:

  • Nephrology
  • Cell Biology
  • Developmental Biology

Background:

  • Wnt ligands are vital for embryonic development and implicated in chronic kidney disease (CKD).
  • The specific cellular origins of Wnt ligands contributing to CKD pathogenesis remain unclear.
  • Wntless (Wls) is essential for Wnt secretion, making it a target for studying Wnt signaling in kidney disease.

Purpose of the Study:

  • To determine the cellular source of Wnt ligands driving kidney fibrosis in CKD.
  • To investigate the role of Wnt secretion from renal tubular epithelial cells versus interstitial fibroblasts in kidney fibrosis.
  • To explore the therapeutic potential of inhibiting Wnt secretion in CKD.

Main Methods:

  • Generated conditional knockout mouse lines with Wntless (Wls) selectively ablated in tubular epithelial cells or interstitial fibroblasts.
  • Utilized unilateral ureteral obstruction and ischemia-reperfusion injury models to induce kidney injury.
  • Assessed renal fibrosis, myofibroblast activation, β-catenin signaling, and tubular integrity.
  • Performed in vitro experiments using normal rat kidney fibroblasts and tubule-derived Wnts.
  • Analyzed kidney biopsy specimens from patients with and without CKD.

Main Results:

  • Genetic deletion of Wls in renal tubules significantly reduced myofibroblast activation and kidney fibrosis following ureteral obstruction.
  • Tubular Wls deletion preserved tubular epithelial integrity and decreased β-catenin signaling.
  • Fibroblast-specific Wls deletion had minimal impact on renal fibrosis severity.
  • In vitro, Wnt ligands from tubular cells promoted fibroblast proliferation and activation.
  • CKD patient kidney tissues showed increased Wnt protein expression, primarily in tubular epithelium.

Conclusions:

  • Renal tubular epithelial cells are a major source of Wnt ligands that promote kidney fibrosis.
  • Tubule-derived Wnts drive kidney fibrosis by activating interstitial fibroblasts through epithelial-mesenchymal communication.
  • Targeting Wnt secretion from renal tubules represents a potential therapeutic strategy for managing CKD.
Keywords:
Wnt signalingWntlesschronic kidney diseasefibroblastrenal fibrosis

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