Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation

Date

2014-02-11
Language
American English

Embargo Lift Date

Committee Members

Degree

Degree Year

Department

Grantor

Journal Title

Journal ISSN

Volume Title

Found At

Ovid Technologies Wolters Kluwer -American Heart Association

Abstract

BACKGROUND: Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease, a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin downregulation or knockout has never been studied before. The present studies aim to examine whether and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin downregulation. METHODS AND RESULTS: Cysts and aneurysms from polycystic kidney disease patients, Pkd mouse, and zebrafish models are characterized by chromosome instability and low survivin expression. This triggers cytokinesis defects and formation of nuclear polyploidy or aneuploidy. In vivo conditional mouse and zebrafish models confirm that survivin gene deletion in the kidneys results in a cystic phenotype. As in hypertensive Pkd1, Pkd2, and Tg737 models, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivin knockout also contributes to abnormal oriented cell division in both kidney and vasculature. Furthermore, survivin expression and ciliary localization are regulated by flow-induced cilia activation through protein kinase C, Akt and nuclear factor-κB. Circumventing ciliary function by re-expressing survivin can rescue polycystic kidney disease phenotypes. CONCLUSIONS: For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in polycystic kidney disease. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm formation and cyst formation share a common cellular and molecular pathway involving cilia function or structure, survivin expression, cytokinesis, cell ploidy, symmetrical cell division, and tissue architecture orientation.

Description

item.page.description.tableofcontents

item.page.relation.haspart

Cite As

AbouAlaiwi, W. A., Muntean, B. S., Ratnam, S., Joe, B., Liu, L., Booth, R. L., … Nauli, S. M. (2014). Survivin-Induced Abnormal Ploidy Contributes to Cystic Kidney and Aneurysm Formation. Circulation, 129(6), 660–672. http://doi.org/10.1161/CIRCULATIONAHA.113.005746

ISSN

1524-4539

Publisher

Series/Report

Sponsorship

Major

Extent

Identifier

Relation

Journal

Circulation

Rights

Publisher Policy

Source

PMC

Alternative Title

Type

Article

Number

Volume

Conference Dates

Conference Host

Conference Location

Conference Name

Conference Panel

Conference Secretariat Location

Version

Author's manuscript

Full Text Available at

This item is under embargo {{howLong}}