Survivin-Induced Abnormal Ploidy Contributes to Cystic Kidney and Aneurysm Formation
- Authors
- Aboualaiwi, W.A., Muntean, B.S., Ratnam, S., Joe, B., Liu, L., Booth, R.L., Rodriguez, I., Herbert, B.S., Bacallao, R.L., Fruttiger, M., Mak, T.W., Zhou, J., and Nauli, S.M.
- ID
- ZDB-PUB-140101-18
- Date
- 2014
- Source
- Circulation 129(6): 660-72 (Journal)
- Registered Authors
- Keywords
- aurora, renal epithelia, vascular endothelia, fluid-shear stress, cardiovascular, calcium, cardivascular disease
- MeSH Terms
-
- Aneuploidy
- Aneurysm/genetics*
- Aneurysm/metabolism
- Aneurysm/pathology
- Animals
- Cell Division/genetics
- Cilia/pathology
- Down-Regulation/genetics
- Humans
- Hypertension/genetics
- Hypertension/metabolism
- Hypertension/pathology
- Inhibitor of Apoptosis Proteins/genetics*
- Inhibitor of Apoptosis Proteins/metabolism
- Kidney Diseases, Cystic/genetics*
- Kidney Tubules, Collecting/cytology*
- Mice
- Mice, Knockout
- NF-kappa B/metabolism
- Phenotype
- Polycystic Kidney, Autosomal Dominant/genetics*
- Polycystic Kidney, Autosomal Dominant/metabolism
- Polycystic Kidney, Autosomal Dominant/pathology
- Primary Cell Culture
- Protein Kinase C/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Repressor Proteins/genetics*
- Repressor Proteins/metabolism
- Urothelium/cytology
- Zebrafish
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 24235270 Full text @ Circulation
Background—Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease (PKD), a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin down-regulation or knockout has never been studied before. The present studies aim to examine if and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin down-regulation.
Methods and Results—Cysts and aneurysms from PKD 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 deletion, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivinknockout 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 PKC, Akt and NF-κB. Circumventing ciliary function by re-expressing survivin can rescue PKD phenotypes.
Conclusions—For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in PKD. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm 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.