RESOLUTION OF GLOMERULOSCLEROSIS

Summary

Principal Investigator: Agnes B Fogo
Abstract: DESCRIPTION (provided by applicant): In the previous funding period, we have shown that high doses of angiotensin inhibition, linked to decreased plasminogen activator inhibitor-1 (PAI-1), could regress existing glomerulosclerosis over the short term. This regression was linked to decreased matrix and restoration of plasmin. Our new preliminary data show limited long-term efficacy over six months of this intervention, indicating limitations of blockade of only the AT1 receptor. We postulate that these limits are due to the inability of podocytes to regenerate and proliferate after injury. We therefore will now focus on the potential and mechanisms of podocyte loss and repair to allow optimal regression of existing glomerulosclerosis. Our new exciting preliminary data shows that PAI-1 deficiency protects podocytes after injury with decreased loss and preserved differentiation. Podocytes deficient in PAI-1 revealed remarkable protection with less apoptosis and preserved cytoskeleton in vitro after injury, and systemic PAI-1 knockout mice were protected from development of sclerosis. Based on these exciting new data, our new central hypothesis is that decreased PAI-1 plays a pivotal role in preventing podocyte loss. Novel exciting data implicate the parietal epithelial cell (PECs) as a niche stem cell for podocyte regeneration, and suggest that these PECS could migrate to a visceral epithelial cell location. However, it is not determined whether these migrating parietal cells contribute to repair or alternatively may promote matrix synthesis and sclerosis. We will explore the mechanisms of podocyte protection by PAI-1 deficiency, testing the hypothesis that podocyte PAI-1 deficiency maintains podocyte number and function, and that this is mediated by decrease in the urokinase type plasminogen activator receptor. We will further test the hypothesis that consequences of parietal epithelial cell transition after injury are modulated by PAI-1. We have in hand homozygous floxed mice to allow us to examine in-depth mechanisms of time-specific deletion of PAI-1 in podocytes specifically both in vivo and in vitro. We will tes these hypotheses in a primary podocyte injury model with a toxin receptor specifically expressed only on podocytes (NEP25), and in a model of secondary sclerosis induced by 5/6 nephrectomy. Together, our studies will examine the potential and mechanisms of long-term regression of glomerulosclerosis, hypothesized to be fundamentally linked to PAI-1-dependent mechanisms that decrease podocyte loss and increase podocyte regeneration.
Funding Period: 1999-12-01 - 2017-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Plasminogen activator inhibitor-1 modulates adipocyte differentiation
    Xiubin Liang
    Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232 2561, USA
    Am J Physiol Endocrinol Metab 290:E103-E113. 2006
  2. pmc Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury
    James M Luther
    Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Kidney Int 82:643-51. 2012
  3. ncbi Pathology of human diabetic nephropathy
    Behzad Najafian
    Department of Pathology, University of Washington, Seattle, Wash, USA
    Contrib Nephrol 170:36-47. 2011
  4. pmc The targeted podocyte
    Agnes B Fogo
    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Clin Invest 121:2142-5. 2011
  5. pmc Sirt1 activation protects the mouse renal medulla from oxidative injury
    Wenjuan He
    Nephrology Division, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee 37232, USA
    J Clin Invest 120:1056-68. 2010
  6. pmc Dystroglycan in the diagnosis of FSGS
    Giovanna Giannico
    C 3310 MCN, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232 2561, USA
    Clin J Am Soc Nephrol 4:1747-53. 2009
  7. ncbi PAI-1 and kidney fibrosis
    Li Jun Ma
    Vanderbilt University Medical Center, Department of Pathology, Nashville, Tennessee, USA
    Front Biosci (Landmark Ed) 14:2028-41. 2009
  8. pmc Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt
    William B Lea
    Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Kidney Int 75:936-44. 2009
  9. pmc Mechanisms of progression of chronic kidney disease
    Agnes B Fogo
    Department of Pathology, Vanderbilt University Medical Center, MCN C3310, Nashville, TN 37232, USA
    Pediatr Nephrol 22:2011-22. 2007
  10. ncbi PPAR-gamma agonist protects podocytes from injury
    T Kanjanabuch
    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Kidney Int 71:1232-9. 2007

Research Grants

Detail Information

Publications16

  1. ncbi Plasminogen activator inhibitor-1 modulates adipocyte differentiation
    Xiubin Liang
    Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232 2561, USA
    Am J Physiol Endocrinol Metab 290:E103-E113. 2006
    ..We postulate that these PAI-1 effects on adipocytes may, at least in part, be mediated via modulation of plasmin activity and extracellular matrix components...
  2. pmc Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury
    James M Luther
    Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Kidney Int 82:643-51. 2012
    ..Thus, mineralocorticoid antagonism may have protective effects in the kidney beyond aldosterone synthase inhibition...
  3. ncbi Pathology of human diabetic nephropathy
    Behzad Najafian
    Department of Pathology, University of Washington, Seattle, Wash, USA
    Contrib Nephrol 170:36-47. 2011
    ..Efforts to develop rodent animal models that more completely capture these key features of human DN will allow advances to be made in understanding pathogenesis and targeting novel treatment...
  4. pmc The targeted podocyte
    Agnes B Fogo
    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Clin Invest 121:2142-5. 2011
    ..In this issue of the JCI, two interesting studies of podocyte-specific manipulation of the mTOR system shed light on the complexity of this pathway in the podocyte...
  5. pmc Sirt1 activation protects the mouse renal medulla from oxidative injury
    Wenjuan He
    Nephrology Division, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee 37232, USA
    J Clin Invest 120:1056-68. 2010
    ..We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress...
  6. pmc Dystroglycan in the diagnosis of FSGS
    Giovanna Giannico
    C 3310 MCN, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232 2561, USA
    Clin J Am Soc Nephrol 4:1747-53. 2009
    ..Fibrosis has been linked to increased fibroblast-specific protein-1 (FSP1) and epithelial-mesenchymal transition. We studied DG, FSP1, and podocyte differentiation in FSGS variants and cases of suspected FSGS...
  7. ncbi PAI-1 and kidney fibrosis
    Li Jun Ma
    Vanderbilt University Medical Center, Department of Pathology, Nashville, Tennessee, USA
    Front Biosci (Landmark Ed) 14:2028-41. 2009
    ..The fibrotic sequelae caused by increased PAI-1 in kidney depend not only on its classic inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA), but also its influence on cell migration...
  8. pmc Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt
    William B Lea
    Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Kidney Int 75:936-44. 2009
    ..Our study shows that mineralocorticoid receptor antagonism and aldosterone synthase inhibition similarly decrease hypertrophy and interstitial fibrosis of the kidney and heart caused by angiotensin II and high salt...
  9. pmc Mechanisms of progression of chronic kidney disease
    Agnes B Fogo
    Department of Pathology, Vanderbilt University Medical Center, MCN C3310, Nashville, TN 37232, USA
    Pediatr Nephrol 22:2011-22. 2007
    ..We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number...
  10. ncbi PPAR-gamma agonist protects podocytes from injury
    T Kanjanabuch
    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Kidney Int 71:1232-9. 2007
    ..We postulate that this protective effect may be mediated in part by effects on p27 and TGF-beta expression...
  11. ncbi Modulation of angiotensin II and norepinephrine-induced plasminogen activator inhibitor-1 expression by AT1a receptor deficiency
    N J Brown
    Vanderbilt University Medical Center, Nashville, Tennessee 37232 6602, USA
    Kidney Int 72:72-81. 2007
    ..We conclude that Ang II stimulates PAI-1 expression in part through the AT(1b) receptor in the kidney and liver. Further, norepinephrine induces PAI-1 expression in vivo with AT(1a) receptor deficiency modulating the effect...
  12. ncbi Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action
    Allison A Eddy
    Children s Hospital and Regional Medical Center, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA
    J Am Soc Nephrol 17:2999-3012. 2006
  13. ncbi Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growth
    Xiu Bin Liang
    Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232 2561, USA
    J Am Soc Nephrol 17:1886-95. 2006
    ..These data support the idea that ARB effects on podocytes may mediate capillary remodeling in vivo...
  14. ncbi Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury
    J Ma
    Division of Pediatric Nephrology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6602, USA
    Kidney Int 69:1064-72. 2006
    ..05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1(-/-) mice. PAI-1 contributes to aldosterone-induced glomerular injury...

Research Grants30

  1. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  2. GENE THERAPY USING HEMATOPOIETIC STEM CELLS
    Donald B Kohn; Fiscal Year: 2013
    ..The Project and Core leaders have complementary expertise in the relevant areas of experimental hematology, gene therapy, immunology, and signal transduction and have a long-standing record of interactive collaborations. ..
  3. A Rational Approach to Stimulating Peripheral Nerve Regeneration Across Criticall
    Ravi V Bellamkonda; Fiscal Year: 2013
    ..abstract_text> ..
  4. 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. ..
  5. Role of primary cilia in corneal development and repair
    Carlo Iomini; Fiscal Year: 2013
    ....
  6. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  8. ALVEOLAR BASEMENT MEMBRANE/CELL INTERACTIONS IN THE LUNG
    Philip L Sannes; Fiscal Year: 2013
    ..This grant will define the specific mechanisms that control this process, and in doing so, enable the development of new and innovative ways to promote the healing process in injured lungs. ..
  9. 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. ..
  10. Development of Adult Pluripotent Very Small Embryonic Like (VSEL) Stem Cells to T
    DENIS OVEREND RODGERSON; Fiscal Year: 2013
    ....
  11. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  12. 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 ..
  13. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  14. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  15. A tissue specific approach to enhance tendon repair
    James H C Wang; Fiscal Year: 2013
    ..Moreover, we will use the proven tendon injury mode in this study as a "stepping-stone" for further studying healing problems of other tendon types, including flexor and rotator cuff tendons. ..
  16. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  17. A temporospatial analysis of epithelial integrity following vocal fold injury
    Ciara Leydon; Fiscal Year: 2013
    ....
  18. Skin Regeneration with Stem Cells and Scaffolds
    SUSAN RENEE OPALENIK; Fiscal Year: 2013
    ..abstract_text> ..