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Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease

Wouter N Leonhard1, Steven J Kunnen1, Anna J Plugge1

  • 1Departments of Human Genetics.

Journal of the American Society of Nephrology : JASN
|March 30, 2016
PubMed

Insights

Activin signaling, not TGF-β, drives polycystic kidney disease (PKD) progression. Blocking activins with a soluble receptor trap significantly reduced cyst formation in mouse models, identifying activin signaling as a potential therapeutic target for PKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing kidney cysts, affecting 0.1% of the population.
  • Current therapies are limited, necessitating new therapeutic targets beyond cAMP reduction.
  • The role of Transforming Growth Factor-beta (TGF-β) signaling in ADPKD is unclear, despite evidence of SMAD2/3 activation in cyst-lining cells.

Purpose of the Study:

  • To investigate the role of TGF-β superfamily ligands in ADPKD pathogenesis.
  • To explore activin signaling as a potential driver of SMAD2/3 activation and cyst formation in ADPKD.
  • To evaluate the therapeutic potential of targeting activin signaling in ADPKD.

Main Methods:

  • Ablation of the TGF-β type 1 receptor (activin receptor-like kinase 5) in renal epithelial cells of PKD mouse models.
  • Analysis of SMAD2/3 target gene expression and PKD progression.
  • Treatment of PKD mouse models with a soluble activin receptor IIB fusion (sActRIIB-Fc) protein to sequester activin ligands.
  • Assessment of cyst formation in response to activin inhibition.

Main Results:

  • Ablating the TGF-β type 1 receptor had minimal impact on SMAD2/3 target genes or PKD progression.
  • Increased expression of activin ligands was observed in mice with PKD, even in early disease stages.
  • Treatment with sActRIIB-Fc effectively inhibited cyst formation across three distinct PKD mouse models.

Conclusions:

  • Activin signaling, rather than TGF-β, is implicated in the pathogenesis of ADPKD.
  • Increased activin levels contribute to SMAD2/3 activation in cystic kidney epithelial cells.
  • Targeting activin signaling with agents like sActRIIB-Fc represents a promising therapeutic strategy for ADPKD.

Keywords:
ADPKDActivinTGF-betagenetic renal diseaseinhbpolycystic kidney disease

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