title: The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis.
abstract: BACKGROUND
  Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure. Aberrant epithelial cell proliferation is a major cause of progressive cyst enlargement in ADPKD. Since activation of the Ras/Raf signaling system has been detected in cyst-lining epithelia, inhibition of Raf kinase has been proposed as an approach to retard the progression of ADPKD. Methods and results. PLX5568, a novel selective small molecule inhibitor of Raf kinases, attenuated proliferation of human ADPKD cyst epithelial cells. It reduced in vitro cyst growth of Madin-Darby Canine Kidney cells and of human ADPKD cells within a collagen gel. In male cy/+ rats with polycystic kidneys, PLX5568 inhibited renal cyst growth along with a significant reduction in the number of proliferating cell nuclear antigen- and phosphorylated extracellular signal-regulated kinase-positive cyst-lining epithelial cells. Furthermore, treated animals showed increased capacity to concentrate urine. However, PLX5568 did not lead to a consistent improvement of renal function. Moreover, although relative cyst volume was decreased, total kidney-to-body weight ratio was not significantly reduced by PLX5568. Further analyses revealed a 2-fold increase of renal and hepatic fibrosis in animals treated with PLX5568.
  
  
  CONCLUSIONS
  PLX5568 attenuated cyst enlargement in vitro and in a rat model of ADPKD without improving kidney function, presumably due to increased renal fibrosis. These data suggest that effective therapies for the treatment of ADPKD will need to target fibrosis as well as the growth of cysts.
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany. bjoern.buchholz@uk-erlangen.de
authors.forename: Bjoern
authors.initials: B
authors.lastname: Buchholz
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: James
authors.initials: J
authors.lastname: Tsai
authors.forename: Sven
authors.initials: S
authors.lastname: Kroening
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshihara
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.forename: Bettina
authors.initials: B
authors.lastname: Kraenzlin
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Peter
authors.initials: P
authors.lastname: Hirth
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Wanja M
authors.initials: WM
authors.lastname: Bernhardt
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003560:Cysts / Q000188:drug therapy / Q000473:pathology*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000139:chemically induced*; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation / Q000187:drug effects; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases