Role of Periostin in Polycystic Kidney Disease

Summary

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

Top Publications

  1. pmc Cyclic AMP-mediated cyst expansion
    Darren P Wallace
    Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
    Biochim Biophys Acta 1812:1291-300. 2011
  2. pmc Ouabain activates the Na-K-ATPase signalosome to induce autosomal dominant polycystic kidney disease cell proliferation
    Anh 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
  3. pmc Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin
    Gail 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
  4. pmc Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl- secretion by human autosomal dominant polycystic kidney cells
    Cibele 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
  5. pmc Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease
    Gustavo Blanco
    Dept of Molecular and Integrative Physiology, 3901 Rainbow Blvd, Kansas City, KS 66160
    Am J Physiol Renal Physiol 305:F797-812. 2013
  6. pmc Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease
    Darren 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
  7. ncbi Retinoic acid signaling pathways in development and diseases
    Bhaskar 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

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
  4. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
  5. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
  6. The Biology of Genetic Variants in Human Kidney Disease
    JOHN F O'TOOLE; Fiscal Year: 2013
  7. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
  8. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
  9. Na,K-ATPase mediated ouabain effects in polycystic kidney disease
    V GUSTAVO BLANCO; Fiscal Year: 2013
  10. Extracellular determinants of polycystic kidney disease severity
    Myron E Hinsdale; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc Cyclic AMP-mediated cyst expansion
    Darren 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...
  2. pmc Ouabain activates the Na-K-ATPase signalosome to induce autosomal dominant polycystic kidney disease cell proliferation
    Anh 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...
  3. pmc Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin
    Gail 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...
  4. pmc Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl- secretion by human autosomal dominant polycystic kidney cells
    Cibele 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...
  5. pmc Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease
    Gustavo Blanco
    Dept of Molecular and Integrative Physiology, 3901 Rainbow Blvd, Kansas City, KS 66160
    Am J Physiol Renal Physiol 305:F797-812. 2013
    ....
  6. pmc Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease
    Darren 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
    ....
  7. ncbi Retinoic acid signaling pathways in development and diseases
    Bhaskar 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
    ....

Research Grants31

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  4. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  5. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  6. The Biology of Genetic Variants in Human Kidney Disease
    JOHN F O'TOOLE; Fiscal Year: 2013
    ..We will test this hypothesis using yeast and murine genetic models of Xpnpep3 deletion to examine its role in the progression of kidney disease and study the mechanisms leading to mTOR activation and defective protein degradation. ..
  7. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  8. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
  9. Na,K-ATPase mediated ouabain effects in polycystic kidney disease
    V GUSTAVO BLANCO; Fiscal Year: 2013
    ....
  10. Extracellular determinants of polycystic kidney disease severity
    Myron E Hinsdale; Fiscal Year: 2013
    ..The proposed research is significant because the identification of genetic modifiers and understanding their impact on clinical variation is expected to advance individualized ARPKD patient treatment and prognostication. ..
  11. The exocyst in kidney development and cyst formation
    BENJAMIN CARL FOGELGREN; Fiscal Year: 2013
    ....
  12. Biobehavioral Foundations and Development of Cognitive Competence
    David A Washburn; Fiscal Year: 2013
    ..RELEVANCE: The findings of these projects will advance our understanding of cognition and its disorders, generating educational interventions and clinical applications with relevance to a wide range of mental health issues. ..
  13. Role of Focal Adhesion Kinase (FAK) in Nephrosis and Nephritis
    Shuta Ishibe; Fiscal Year: 2013
    ..The goal of the proposal is to define the mechanisms that are involved during kidney injury and to utilize inhibitors that antagonize against the offending agent(s) responsible for disease progression. ..