VEGF(165) mediates glomerular endothelial repair.
VEGF(165), the most abundant isoform in man, is an angiogenic cytokine that also regulates vascular permeability. Its function in the renal glomerulus, where it is expressed in visceral epithelial and mesangial cells, is unknown. To assess the role of VEGF(165) in glomerular disease, we administered a novel antagonist - a high-affinity, nuclease-resistant RNA aptamer coupled to 40-kDa polyethylene glycol (PEG) - to normal rats and to rats with mesangioproliferative nephritis, passive Heymann nephritis (PHN), or puromycin aminonucleoside nephrosis (PAN). In normal rats, antagonism of VEGF(165) for 21 days failed to induce glomerular pathology or proteinuria. In rats with mesangioproliferative nephritis, the VEGF(165) aptamer (but not a sequence-scrambled control RNA or PEG alone) led to a reduction of glomerular endothelial regeneration and an increase in endothelial cell death, provoking an 8-fold increase in the frequency of glomerular microaneurysms by day 6. In contrast, early leukocyte influx and the proliferation, activation, and matrix accumulation of mesangial cells were not affected in these rats. In rats with PHN or PAN, administration of the VEGF(165) aptamer did not influence the course of proteinuria using various dosages and administration routes. These data identify VEGF(165) as a factor of central importance for endothelial cell survival and repair in glomerular disease, and point to a potentially novel way to influence the course of glomerular diseases characterized by endothelial cell damage, such as various glomerulonephritides, thrombotic microangiopathies, or renal transplant rejection.
Ostendorf
T
T
Division of Nephrology, Medizinische Hochschule, 30623 Hannover, Germany.
Kunter
U
U
Eitner
F
F
Loos
A
A
Regele
H
H
Kerjaschki
D
D
Henninger
D D
DD
Janjic
N
N
Floege
J
J
D000783:Aneurysm / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology*; D015432:Glomerulonephritis, Membranoproliferative / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D008222:Lymphokines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D020033:Protein Isoforms / Q000493:pharmacokinetics / Q000494:pharmacology; D011507:Proteinuria; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012079:Renal Circulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011092:Polyethylene Glycols; D011692:Puromycin Aminonucleoside