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Src Inhibition Ameliorates Polycystic Kidney Disease

William E. Sweeney, Jr^*, Rodo O. von Vigier, Philip Frost and Ellis D. Avner^*

^* Children's Research Institute, Children's Hospital Health System of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin; Pediatric Nephrology, University Children's Hospital, Berne, Switzerland; and Wyeth Research, Pearl River, New Jersey

Correspondence: Dr. Ellis D. Avner, Children's Research Institute, Children's Hospital Health System of Wisconsin, Medical College of Wisconsin, Children's Corporate Center, Suite C-730, Mailstop CCC C730, 999 North 92nd Street, Wauwatosa, WI 53226. Phone: 414-337-7702; Fax: 414-337-7105; E-mail: eavner{at}mcw.edu

Received for publication June 13, 2007. Accepted for publication February 2, 2008.

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.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673