Effect of maternal administration of selective cyclooxygenase (COX)-2 inhibitors on renal size, growth factors, proteinases, and COX-2 secretion in the fetal rabbit.
BACKGROUND
Selective cyclooxygenase (COX)-2 inhibitors are currently being considered for management of preterm labor. COX-2 is an important regulator of fetal renal growth and function. Its inhibition may lead to congenital oligonephropathy.


OBJECTIVE
We investigated whether maternal administration of a selective COX-2 inhibitor would adversely affect fetal renal growth.


METHODS
Three groups of timed pregnant rabbits at 13 days gestation were examined. Group 1 received oral celecoxib (30 mg/kg/day) from 13 to 20 days gestation (Cel-A); group 2 received celecoxib from 13 to 28 days gestation (Cel-B), and group 3 received equivalent volumes of the vehicle from 13 to 28 days gestation. The fetuses were delivered by cesarean section at 29 days gestation. The kidneys were weighed and analyzed for vascular endothelial growth factor (VEGF) and its soluble receptors, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, COX-2, and total cellular protein levels. Sections from the cortex and medulla were assessed histologically.


RESULTS
Fetal kidney size was unaffected. VEGF levels were elevated in the Cel-B group. Soluble VEGF receptors, MMP-2, TIMP-1 and COX-2 levels remained unchanged. MMP-9 levels were suppressed in both treated groups, which resulted in significantly lower MMP-9/TIMP-1 ratios. Although TIMP-2 secretion was enhanced in the Cel-B group, MMP-2/TIMP-2 ratios were unaffected. No significant histological changes were detected.


CONCLUSIONS
We conclude that maternal administration of therapeutic doses of celecoxib does not adversely affect fetal renal growth. MMP-9 is increased in various nephropathies, but may also have protective effects therefore its suppression by COX-2 inhibitors needs further study.
Hartleroad
Jeffrey Y
JY
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Irvine Medical Center, University of California, Orange, CA 92868, USA.
Beharry
Kay D
KD
Hausman
Nicole
N
Stavitsky
Yuri
Y
Asrat
Tamerou
T
Modanlou
Houchang D
HD
D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D006651:Histocytochemistry; D007668:Kidney / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism; D018811:Maternal Exposure; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D007752:Obstetric Labor, Premature / Q000517:prevention & control; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D040262:Receptors, Vascular Endothelial Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib