Src inhibition ameliorates polycystic kidney disease.
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.
Sweeney
William E
WE
Children's Research Institute, Children's Hospital Health System of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
von Vigier
Rodo O
RO
Frost
Philip
P
Avner
Ellis D
ED
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases
D000814:Aniline Compounds; D000242:Cyclic AMP; D066246:ErbB Receptors; D006023:Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D048493:Proto-Oncogene Proteins B-raf; D016392:Proto-Oncogene Proteins pp60(c-src); D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C471992:bosutinib; C483804:Erbb2 protein, rat