Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol 2008 Jul;19(7):1331-41
Date
04/04/2008Pubmed ID
18385429Pubmed Central ID
PMC2440293DOI
10.1681/ASN.2007060665Scopus ID
2-s2.0-48149104099 (requires institutional sign-in at Scopus site) 131 CitationsAbstract
Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60(c-Src)) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Src-mediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.
Author List
Sweeney WE Jr, von Vigier RO, Frost P, Avner EDAuthor
Ellis D. Avner MD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Aniline CompoundsAnimals
Cyclic AMP
Disease Progression
ErbB Receptors
Glycoproteins
Kidney
Kidney Function Tests
MAP Kinase Signaling System
Male
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Nitriles
Organ Size
Polycystic Kidney, Autosomal Recessive
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins pp60(c-src)
Quinolines
Rats
Rats, Sprague-Dawley
Receptor, ErbB-2
