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Src inhibition ameliorates polycystic kidney disease

William E Sweeney1, Rodo O von Vigier, Philip Frost

  • 1Children's Research Institute, Children's Hospital Health System of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Journal of the American Society of Nephrology : JASN
|April 4, 2008
PubMed

Insights

Src inhibition may treat polycystic kidney disease (PKD). This study found that inhibiting Src activity reduced cyst formation and biliary abnormalities in ARPKD models, suggesting a new therapeutic target for PKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Autosomal dominant and recessive polycystic kidney diseases (PKD) lack targeted therapies due to unknown cystoprotein functions.
  • Aberrant signaling cascades initiated by cystoprotein complexes are implicated in PKD pathogenesis.
  • Identifying common signaling intermediates presents potential therapeutic targets.

Purpose of the Study:

  • To investigate the role of c-Src (pp60(c-Src)) activity in polycystic kidney disease (PKD) cystogenesis.
  • To determine if Src inhibition can ameliorate PKD phenotypes in animal models.

Main Methods:

  • Utilized nonorthologous BPK murine and orthologous PCK rat models of autosomal recessive PKD (ARPKD).
  • Assessed Src activity in relation to disease progression.
  • Administered the pharmacologic Src inhibitor SKI-606 to evaluate its therapeutic effects.

Main Results:

  • Elevated Src activity correlated with disease progression in both ARPKD models.
  • SKI-606 treatment significantly reduced renal cyst formation and biliary ductal abnormalities.
  • Src inhibition in PCK rat kidneys involved ErbB2 and B-Raf/MEK/ERK pathways without affecting cAMP levels.

Conclusions:

  • Src activity is a key mediator of cyst formation in ARPKD.
  • Pharmacologic inhibition of Src demonstrates therapeutic potential for PKD.
  • Targeting Src signaling offers a promising strategy for treating polycystic kidney diseases.

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