Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

Journal of the American Society of Nephrology : JASN
Holger LehmannIan J Frew

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 displa...Continue Reading

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Citations

Apr 30, 2016·The Journal of Pathology·Anna GuinotIan J Frew
Nov 5, 2016·PloS One·Andrew Resnick
Jul 12, 2017·Nature Medicine·Laura S Schmidt, W Marston Linehan
Sep 29, 2018·Human Molecular Genetics·Sarah E ConduitChristina A Mitchell
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Dec 10, 2019·Cellular Signalling·Christine PodriniAlessandra Boletta
Feb 25, 2020·Translational Oncology·Paweł SobczukAnna M Czarnecka
Apr 2, 2021·Kidney International·Anna Julie PeiredPaola Romagnani

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