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


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.
Department of Pharmacology (W.A.A., S.M.N.), Department of Medicinal and Biological Chemistry (B.S.M., S.M.N.), Department of Medicine (S.R., S.M.N.), Center for Hypertension and Personalized Medicine (B.J., S.M.N.), Department of Biochemistry and Cancer Biology (L.L.), and Department of Pathology (R.L.B.), University of Toledo, Toledo, OH; Department of Emergency and Intensive Care, ProMedica Sponsored Research, Toledo, OH (I.R.); Departments of Medicine (B.S.H.) and Medical and Molecular Genetics (R.L.B.), Indiana University School of Medicine, Indianapolis; UCL Institute of Ophthalmology, University College London, London, UK (M.F.); Ontario Cancer Institute, University Health Network, Toronto, ON, Canada (T.W.M.); and Department of Medicine, Brigham and Women's Hospital, Boston, MA (J.Z.).
Wissam A
WA
Aboualaiwi
Brian S
BS
Muntean
Shobha
S
Ratnam
Bina
B
Joe
Lijun
L
Liu
Robert L
RL
Booth
Ingrid
I
Rodriguez
Britney S
BS
Herbert
Robert L
RL
Bacallao
Marcus
M
Fruttiger
Tak W
TW
Mak
Jing
J
Zhou
Surya M
SM
Nauli
D000782:Aneuploidy; D000783:Aneurysm / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000235:genetics; D002923:Cilia / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D007685:Kidney Tubules, Collecting / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin; D019459:Urothelium / Q000166:cytology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C541681:Birc5a protein, zebrafish; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D000077022:Survivin; D029961:Zebrafish Proteins; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C
aurora kinase; blood flow; blood pressure; cardiovascular system; endothelium, vascular; epithelium