Kidney Week

Abstract: SA-OR094

Aurora A Kinase Is Required for Development of Renal Cysts in a Ciliopathy Model

Session Information

• Pathogenesis of Cystic Kidney Diseases
  November 09, 2019 | Location: 143, Walter E. Washington Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Smyth, Ian, Monash University, Clayton, Victoria, Australia

Ian Smyth, PhD



Professor Ian Smyth is an NH&MRC Senior Research Fellow at Monash University in Melbourne, Australia. He co-heads the Development and Stem Cells Program at the Monash Biomedicine Institute and is the Deputy Head (Research) of the Department of Anatomy and Developmental Biology. His doctoral studies at the University of Queensland focused on understanding the role of the PATCHED genes in human disease. He then undertook postdoctoral work in Edinburgh, Houston and London using forward genetic screens in mice to identify novel genes involved in skin and kidney development and disease. His group’s work focuses on two specific questions: how development of the fetal renal collecting duct system is impacted by genetic mutation and environmental perturbation and how disruption of signaling in these cells in the adult kidney gives rise to cysts in ciliopathy patients.

• Cottle, Denny L., Monash University, Clayton, Victoria, Australia

Denny L. Cottle,

• Tham, Mingshen, Monash University, Clayton, Victoria, Australia

Mingshen Tham,

• Zylberberg, Allara, Monash University, Clayton, Victoria, Australia

Allara Zylberberg,

• Jones, Lynelle K., Monash University, Clayton, Victoria, Australia

Lynelle K. Jones,

• Short, Kieran M., Monash University, Clayton, Victoria, Australia

Kieran M. Short,

• Conduit, Sarah E., Monash University, Clayton, Victoria, Australia

Sarah E. Conduit,

• Mitchell, Christina Anne, Monash University, Clayton, Victoria, Australia

Christina Anne Mitchell,

Background

Aurora A Kinase (AURKA) is classically regarded as a mitotic cell kinase necessary for progression through the cell cycle. It is also associated with disassembly of the primary cilium. We have previously shown that in vitro inhibition of AURKA is sufficient to reverse many of the cyst associated phenotypes in cultured cells lacking the Joubert Syndrome gene, INPP5E. This raises the possibility that therapies aimed at limiting AURKA actions may represent an approach to preventing cyst development in this and other ciliopathies.

Methods

To investigate a casuative role for AURKA in renal cyst initiation and progression we have independently inhibited its kinase activity (using Alisertib) and deleted the Aurka gene in a mouse model of PKD development in Joubert Syndrome. We have then studied the impact of these alterations on cystogenesis and cell signaling.

Results

We find that treatment with Alisertib results in the generation of more, rather than less, renal cysts and provide evidence that the drug actually increases the amount of AURKA protein in kidney cells. Conversely, we find the while AURKA deletion does not affect the development or homeostasis of the collecting duct system, its co-deletion with Inpp5e is able to almost completely prevent PKD - over the long term. Analysis of these models indicates that AURKA over-expression in PKD is associated with increased AKT signalling and that genetic deletion of AURKA normalises this pathway and cyst associated DNA damage. Furthermore, we find that AKT and AURKA directly interact and co-localise to the primary cilium in a dynamic manner associated with the activation of growth factor signaling.

Conclusion

These studies demonstrate that while AURKA is dispensible for renal development and tubule homeostasis, it acts as a key driver of cyst formation. The failure of Alisertib to ameliorate cyst formation contrasts with the profound prevention of disease mediated by AURKA gene deletion. Taken together, these findings that suggest that kinase independent functions of AURKA are central to cystogenesis. The correction of AKT signaling and the close functional association identified between AURKA and AKT highlights dysregulation of this pathway as being critically important for cyst initiation, suggesting a potential avenue for therapeutic development.

Funding

• Government Support - Non-U.S.