title: Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation.
abstract: A subset of familial and sporadic clear cell renal cell carcinomas (ccRCCs) is believed to develop from cystic precursor lesions. Loss of function of the von Hippel-Lindau tumor suppressor gene (VHL) predisposes renal epithelial cells to loss of the primary cilium in response to specific signals. Because the primary cilium suppresses renal cyst formation, loss of the cilium may be an initiating event in the formation of ccRCC. To test this hypothesis, we analyzed the consequences of inducible renal epithelium-specific deletion of Vhl together with ablation of the primary cilium via deletion of the kinesin family member 3A (Kif3a) gene. We developed a microcomputed tomography-based imaging approach to allow quantitative longitudinal monitoring of cystic burden, revealing that combined loss of Vhl and Kif3a shortened the latency of cyst initiation, increased the number of cysts per kidney, and increased the total cystic burden. In contrast with findings in other cystic models, cysts in Kif3a mutant mice did not display accumulation of hypoxia-inducible factor 1-α (HIF1α), and deletion of both Hif1a and Kif3a did not affect cyst development or progression. Vhl/Kif3a double mutation also increased the frequency of cysts that displayed multilayered epithelial growth, which correlated with an increased frequency of misoriented cystic epithelial cell divisions. These results argue against the involvement of HIF1α in promoting renal cyst growth and suggest that the formation of simple and atypical renal cysts that resemble ccRCC precursor lesions is greatly accelerated by the combined loss of Vhl and the primary cilium.
authors: Institute of Physiology and.
authors: Holger
authors: H
authors: Lehmann
authors: Institute of Physiology and.
authors: Daniele
authors: D
authors: Vicari
authors: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors: Peter J
authors: PJ
authors: Wild
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; and ian.frew@access.uzh.ch.
authors: Ian J
authors: IJ
authors: Frew
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D017353:Gene Deletion; D005838:Genotype; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D016547:Kinesins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000502:physiology; D055114:X-Ray Microtomography; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019426:Integrases; D016547:Kinesins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C490202:Kif3a protein, mouse; C045073:Cre recombinase; C494469:VHL protein, mouse
keywords: cell biology and structure; cystic kidney; renal carcinoma