Kidney vascularization: semaphorin-mediated mechanisms.

Summary

Principal Investigator: Alda Tufro
Affiliation: Yale University
Country: USA
Abstract: DESCRIPTION (provided by applicant): The molecular basis of directional migration of endothelial cells and the patterning of the developing vasculature during kidney organogenesis are poorly understood. We showed that VEGF is a chemoattractant for endothelial cells and directs the migration of endothelial cells towards developing nephrons. Other guidance cues are necessarily involved to modulate vascular growth. The nature of these guidance cues is unknown. Two VEGF co-receptors, neuropilins 1 and 2 are also receptors for semaphorins 3A and 3F. Semaphorins are guidance proteins that induce axon chemorepulsion. Sema 3A decreases endothelial cell migration by competing with VEGF for neuropilin binding. We showed that sema 3A and 3F are expressed during renal morphogenesis and localize to renal epithelial cells in a complementary fashion to their receptors located in endothelial cells, suggesting that semaphorins are important for vascular patterning. The objectives of this proposal are to elucidate the mechanisms of endothelial cells directional migration leading to the spatial organization of the developing vasculature and the function of semaphorins 3A and 3F during kidney morphogenesis. We hypothesize that sema 3A and 3F produced by renal epithe!ial cells generate chemorepulsive cues that modulate VEGF's endothelial cell chemoattraction by creating boundaries to endothelial cell migration. The combinatorial possibilities of ligand binding for sema 3 A, sema 3F and VEGF to their shared receptors may result in "paths" for vessel formation. We also hypothesize that the scatter factor-like properties of semaphorins may be responsible, at least in part, for branching morphogenesis of renal epithelia. To test our hypotheses: 1) we will study the mechanims of sema 3A and sema 3F guidance cues for endothelial cell migration by live cell microscopy using co-culture, migration assays, and cell-specific overexpression of sema 3A and 3F in transgenic mice. 2) We will examine the function of semaphorins 3A and 3F in branching morphogenesis and tubulogenesis using tubular epithelial cells, organ cultures and transgenic mice. 3) We will examine the role of FAK and the downstream signaling mechanisms involved in semaphorin-mediated guidance and morphogenetic cues. This proposal should provide novel and important information regarding semaphorin-induced directional migration and advance our knowledge of the molecular mechanisms governing vascular spatial organization. Understanding the molecular basis of guidance cues for cell migration should enable us to generate new strategies for diagnosis and treatment of congenital renal abnormalities and to develop organogenesis in vitro.
Funding Period: 2003-03-10 - 2009-01-31
more information: NIH RePORT

Top Publications

  1. pmc Semaphorin3a signaling, podocyte shape, and glomerular disease
    Alda Tufro
    Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, CT, 06520 8064, USA
    Pediatr Nephrol 29:751-5. 2014
  2. pmc Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction
    Kimberly J Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York
    Am J Pathol 183:1156-68. 2013
  3. pmc VEGF and podocytes in diabetic nephropathy
    Alda Tufro
    Department of Pediatrics, Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520 8064, USA
    Semin Nephrol 32:385-93. 2012
  4. pmc Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk
    Kimberly Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
    Pediatr Nephrol 26:1407-12. 2011
  5. pmc Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development
    Kimberly J Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
    Development 136:3979-89. 2009
  6. pmc Semaphorin3a inhibits ureteric bud branching morphogenesis
    Alda Tufro
    Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 708, Bronx, NY 10461, USA
    Mech Dev 125:558-68. 2008
  7. ncbi Semaphorin3a disrupts podocyte foot processes causing acute proteinuria
    R Tapia
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Kidney Int 73:733-40. 2008
  8. ncbi Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways
    Alda Tufro
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Biochem Biophys Res Commun 358:410-6. 2007
  9. ncbi Semaphorin 3C regulates endothelial cell function by increasing integrin activity
    Nazifa Banu
    Division of Nephrology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 USA
    FASEB J 20:2150-2. 2006
  10. ncbi Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP
    Fangxia Guan
    Dept of Pediatrics Nephrology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Forchheimer Bldg, Rm 708, Bronx, NY 10461, USA
    Am J Physiol Renal Physiol 291:F422-8. 2006

Scientific Experts

  • A Tufro
  • Kimberly J Reidy
  • Guillermo Villegas
  • Jason Teichman
  • F Guan
  • Delma Veron
  • Kimberly Reidy
  • R Tapia
  • J Teichman
  • G Villegas
  • Fangxia Guan
  • Nazifa Banu
  • Juan J Jimenez
  • Pardeep K Aggarwal
  • David B Thomas
  • Wa Shen
  • David Thomas
  • Juan Jimenez
  • I Gershin
  • P Mundel
  • Peter Mundel
  • Marya Dunlap-Brown

Detail Information

Publications11

  1. pmc Semaphorin3a signaling, podocyte shape, and glomerular disease
    Alda Tufro
    Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, CT, 06520 8064, USA
    Pediatr Nephrol 29:751-5. 2014
    ..Nephrin-plexinA1 interaction links the slit-diaphragm signaling complex to extracellular sema3a signals. Hence, sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier. ..
  2. pmc Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction
    Kimberly J Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York
    Am J Pathol 183:1156-68. 2013
    ..Our findings demonstrate a crosstalk between Sema3a and nephrin signaling pathways that is functionally relevant both in vivo and in vitro...
  3. pmc VEGF and podocytes in diabetic nephropathy
    Alda Tufro
    Department of Pediatrics, Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520 8064, USA
    Semin Nephrol 32:385-93. 2012
    ..Recent findings on these pathogenic molecular mechanisms provide new potential targets for therapy for diabetic renal disease...
  4. pmc Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk
    Kimberly Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
    Pediatr Nephrol 26:1407-12. 2011
    ..Understanding the signaling pathways downstream from semaphorin receptors will provide insight into the mechanism of action of semaphorins in renal pathology...
  5. pmc Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development
    Kimberly J Reidy
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
    Development 136:3979-89. 2009
    ..Hence, a tight regulation of Sema3a dosage is required for the establishment of a normal glomerular filtration barrier...
  6. pmc Semaphorin3a inhibits ureteric bud branching morphogenesis
    Alda Tufro
    Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 708, Bronx, NY 10461, USA
    Mech Dev 125:558-68. 2008
    ..Collectively, these data suggest that Sema3a is an endogenous antagonist of ureteric bud branching and hence, plays a role in patterning the renal collecting system as a negative regulator...
  7. ncbi Semaphorin3a disrupts podocyte foot processes causing acute proteinuria
    R Tapia
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Kidney Int 73:733-40. 2008
    ..Our findings indicate that a balance of semaphorin3a to vascular endothelial growth factor-A may be important for glomerular filtration barrier homeostasis...
  8. ncbi Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways
    Alda Tufro
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Biochem Biophys Res Commun 358:410-6. 2007
    ..These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells...
  9. ncbi Semaphorin 3C regulates endothelial cell function by increasing integrin activity
    Nazifa Banu
    Division of Nephrology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 USA
    FASEB J 20:2150-2. 2006
    ....
  10. ncbi Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP
    Fangxia Guan
    Dept of Pediatrics Nephrology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Forchheimer Bldg, Rm 708, Bronx, NY 10461, USA
    Am J Physiol Renal Physiol 291:F422-8. 2006
    ..VEGF-A functions in podocytes include promoting survival through VEGFR2, inducing podocin upregulation and increasing podocin/CD2AP interaction...
  11. ncbi Autocrine class 3 semaphorin system regulates slit diaphragm proteins and podocyte survival
    F Guan
    Department of Pediatrics and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA
    Kidney Int 69:1564-9. 2006
    ....