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

Wissam A. Abou Alaiwi, Brian S. Muntean, Shobha Ratnam, Bina Joe, Lijun Liu, Robert L. Booth, Ingrid Rodriguez, Brittney-Shea Herbert, Robert Bacallao, Marcus Fruttiger, Tak W. Mak, Jing Zhou, Surya M. Nauli

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)660-672
Number of pages13
JournalCirculation
Volume129
Issue number6
DOIs
StatePublished - Feb 11 2014

Fingerprint

Cystic Kidney Diseases
Ploidies
Aneurysm
Cilia
Polycystic Kidney Diseases
Blood Vessels
Cytokinesis
Zebrafish
Phenotype
Kidney
Cell Division
Cysts
Down-Regulation
Hypertension
Chromosomal Instability
Clinical Pathology
Polyploidy
Gene Deletion
Aneuploidy
Protein Kinase C

Keywords

  • Aurora kinase
  • Blood flow
  • Blood pressure
  • Cardiovascular system
  • Endothelium
  • Epithelium
  • Vascular

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Abou Alaiwi, 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. https://doi.org/10.1161/CIRCULATIONAHA.113.005746

Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. / Abou Alaiwi, Wissam A.; Muntean, Brian S.; Ratnam, Shobha; Joe, Bina; Liu, Lijun; Booth, Robert L.; Rodriguez, Ingrid; Herbert, Brittney-Shea; Bacallao, Robert; Fruttiger, Marcus; Mak, Tak W.; Zhou, Jing; Nauli, Surya M.

In: Circulation, Vol. 129, No. 6, 11.02.2014, p. 660-672.

Research output: Contribution to journalArticle

Abou Alaiwi, WA, Muntean, BS, Ratnam, S, Joe, B, Liu, L, Booth, RL, Rodriguez, I, Herbert, B-S, Bacallao, R, Fruttiger, M, Mak, TW, Zhou, J & Nauli, SM 2014, 'Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation', Circulation, vol. 129, no. 6, pp. 660-672. https://doi.org/10.1161/CIRCULATIONAHA.113.005746
Abou Alaiwi WA, Muntean BS, Ratnam S, Joe B, Liu L, Booth RL et al. Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. Circulation. 2014 Feb 11;129(6):660-672. https://doi.org/10.1161/CIRCULATIONAHA.113.005746
Abou Alaiwi, Wissam A. ; Muntean, Brian S. ; Ratnam, Shobha ; Joe, Bina ; Liu, Lijun ; Booth, Robert L. ; Rodriguez, Ingrid ; Herbert, Brittney-Shea ; Bacallao, Robert ; Fruttiger, Marcus ; Mak, Tak W. ; Zhou, Jing ; Nauli, Surya M. / Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. In: Circulation. 2014 ; Vol. 129, No. 6. pp. 660-672.
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AU - Rodriguez, Ingrid

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