title: Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism.
abstract: BACKGROUND
  Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function.
  
  
  METHODS
  To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA).
  
  
  RESULTS
  Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes.
  
  
  CONCLUSIONS
  ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss., USA.
authors.forename: Taylor W
authors.initials: TW
authors.lastname: Harvey
authors.forename: Jason E
authors.initials: JE
authors.lastname: Engel
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050199:Podocytes; D065840:Protective Factors; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1