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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
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
Summary
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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