Genomes and Genes
RESOLUTION OF GLOMERULOSCLEROSIS
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
- Plasminogen activator inhibitor-1 modulates adipocyte differentiationXiubin 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...
- Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injuryJames 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...
- Pathology of human diabetic nephropathyBehzad 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...
- The targeted podocyteAgnes 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...
- Sirt1 activation protects the mouse renal medulla from oxidative injuryWenjuan 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...
- Dystroglycan in the diagnosis of FSGSGiovanna 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...
- PAI-1 and kidney fibrosisLi 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...
- Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high saltWilliam 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...
- Mechanisms of progression of chronic kidney diseaseAgnes 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...
- PPAR-gamma agonist protects podocytes from injuryT 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...
- Modulation of angiotensin II and norepinephrine-induced plasminogen activator inhibitor-1 expression by AT1a receptor deficiencyN 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...
- Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of actionAllison 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
- Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growthXiu 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...
- Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injuryJ 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...
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