Genomes and Genes
Role of Periostin in Polycystic Kidney Disease
Principal Investigator: Darren P Wallace
Abstract: DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a hyperplastic disorder in which aberrant growth of tubule epithelial cells causes the formation of numerous fluid-filled cysts, massively enlarged kidneys and progressive loss of renal function. Although cysts are benign neoplasms, they ultimately cause renal insufficiency through extensive nephron loss and replacement of adjacent parenchyma with fibrosis. The mechanisms by which cysts destroy the kidneys are poorly understood;however changes in the deposition of the extracellular matrix (ECM) are likely to be important. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was over expressed 15-fold compared to normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts as a soluble ECM molecule, is not expressed in normal adult kidneys but is expressed transiently during renal development within the nephrogenic zone, a site of nephron formation and vascularization. In ADPKD, periostin was expressed in cyst-lining cells in situ, in extracellular matrix adjacent to the cysts and within cyst fluid. Expression of aV-integrin, a receptor for periostin, was 9-fold higher in ADPKD cells compared to NHK cells, and antibodies that block aV-integrin inhibited periostin-induced cell proliferation. By contrast, periostin did not affect the proliferation of normal kidney cells. We found that periostin activates integrin-linked kinase (ILK), a kinase that regulates cell proliferation and survival through activation of Akt, GSK-32/2-catenin and mTOR signaling pathways. In preliminary data, we found that periostin expression was elevated in the kidneys of pcy/pcy and Pkd2WS25/- mice, models of human PKD;and that genetic knockout of periostin (PN-/-) reduced kidney weight (as a % of body weight) in the pcy/pcy mouse. We also found that periostin levels were elevated sera of non-azotemic ADPKD patients (n = 14) compared to normal volunteers (n = 8), suggesting that periostin may be an early indicator of PKD progression. Our general hypothesis is that periostin is a novel autocrine mitogen with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD. PUBLIC HEALTH RELEVANCE: ADPKD is the most frequently inherited kidney disorder with a gene frequency of 1 in 500 to 1,000 births and accounts for approximately 5-9% of all end-stage renal diseases. Costs for renal transplantation, dialysis and related treatments for PKD approach $2 billion/yr in the US alone and it is estimated that by the end of this decade treatments will cost $90 billion/yr worldwide. Completion of the proposed studies will provide new information on the role of periostin, a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.
Funding Period: 2009-08-21 - 2014-07-31
more information: NIH RePORT
- Cyclic AMP-mediated cyst expansionDarren P Wallace
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
Biochim Biophys Acta 1812:1291-300. 2011..This article is part of a Special Issue entitled: Polycystic Kidney Disease...
- Ouabain activates the Na-K-ATPase signalosome to induce autosomal dominant polycystic kidney disease cell proliferationAnh Nguyet T Nguyen
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
Am J Physiol Renal Physiol 301:F897-906. 2011..Altogether, these results identify intracellular pathways of ouabain-dependent Na-K-ATPase-mediated signaling in ADPKD cells, including EGFR-Src-B-Raf-MEK/ERK, and establish novel mechanisms involved in ADPKD cell proliferation...
- Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressinGail A Reif
Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160 3018, USA
Am J Physiol Renal Physiol 301:F1005-13. 2011..These data demonstrate that relatively low concentrations of tolvaptan inhibit AVP-stimulated cell proliferation and Cl(-)-dependent fluid secretion by human ADPKD cystic cells...
- Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl- secretion by human autosomal dominant polycystic kidney cellsCibele S Pinto
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160 3018, USA
Am J Physiol Renal Physiol 303:F1412-24. 2012..We suggest that a compensatory response to decreased Ca(2+) in ADPKD cells switches V2R coupling from Ca(2+)-inhibited ACs 5/6 to Ca(2+)/CaM-stimulated AC3, to mitigate high cAMP levels in response to continuous AVP stimulation...
- Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney diseaseGustavo Blanco
Dept of Molecular and Integrative Physiology, 3901 Rainbow Blvd, Kansas City, KS 66160
Am J Physiol Renal Physiol 305:F797-812. 2013....
- Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney diseaseDarren P Wallace
1 Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA 2 Department of Molecular and Integrative Physiology, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
Kidney Int 85:845-54. 2014....
- Retinoic acid signaling pathways in development and diseasesBhaskar C Das
Division of Hematology and Oncology, Department of Internal Medicine, Kansas University Medical Center, Kansas City, KS 66103, USA Molecular Bio nanotechnology, Imaging and Therapeutic Research Unit, Veteran Affairs Medical Center, Kansas City, MO 64128, USA Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA The Kidney Institute, Department of Internal Medicine, Kansas University Medical Center, Kansas City, KS 66103, USA Electronic address
Bioorg Med Chem 22:673-83. 2014....
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