ABSTRACT
Indomethacin and ibuprofen are administered to close a patent ductus arteriosus (PDA) during active glomerulogenesis. Light and electron microscopic glomerular changes with no change in glomerular number were seen following indomethacin and ibuprofen treatment during glomerulogenesis at 14 days after birth in a neonatal rat model. This present study aimed to determine whether longstanding renal structural changes are present at 30 days and 6 mo (equivalent to human adulthood). Rat pups were administered indomethacin or ibuprofen antenatally on days 18-20 (0.5 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen). Control groups received no treatment or normal saline intraperitoneally. Pups were killed at 30 days of age and 6 mo of age. Tissue blocks from right kidneys were prepared for light and electron microscopic examination, while total glomerular number was determined in left kidneys using unbiased stereology. Eight pups were included in each group from 14 maternal rats. At 30 days and 6 mo, there were persistent electron microscopy abnormalities of the glomerular basement membrane in those receiving postnatal indomethacin and ibuprofen. There were no significant light microscopy findings at 30 days or 6 mo. At 6 mo, there were significantly fewer glomeruli in those receiving postnatal indomethacin but not ibuprofen (P = 0.003). In conclusion, indomethacin administered during glomerulogenesis appears to reduce the number of glomeruli in adulthood. Alternative options for closing a PDA should be considered including ibuprofen as well as emerging therapies such as paracetamol.
Subject(s)
Cyclooxygenase Inhibitors/adverse effects , Ibuprofen/adverse effects , Indomethacin/adverse effects , Kidney Glomerulus/drug effects , Tocolytic Agents/adverse effects , Animals , Animals, Newborn , Body Weight/drug effects , Female , Kidney Glomerulus/embryology , Kidney Glomerulus/ultrastructure , Pregnancy , Rats, Sprague-DawleyABSTRACT
BACKGROUND: The exact molecular mechanisms that regulate ureteric branching morphogenesis in the developing metanephros have not been fully elucidated. However, in vivo and in vitro evidence indicates that glial cell line-derived neurotrophic factor (GDNF) is a key regulator of the initiation of ureteric branching. GDNF knockout mice show renal agenesis or severe dysgenesis and die 24 hours after birth from renal failure. Inhibition of GDNF activity in metanephric organ culture inhibits ureteric branching. Since nephron initiation only occurs at the tips of ureteric branches, the aim of the present study was to determine whether nephron number in GDNF heterozygous mice is reduced. METHODS: Male GDNF heterozygous mice of hybrid 129/Sv and C57/BL genetic background were mated with C57BL/6 females. Offspring were genotyped at postnatal day 30 (PN30) by polymerase chain reaction. Left kidneys were used for estimating kidney volume and total nephron number. We also estimated absolute and relative volumes of ureteric duct epithelium. Unbiased stereological methods were used throughout (Cavalieri method, physical disector/fractionator combination). RESULTS: GDNF wild-type and heterozygous mice had similar body weights at PN30. However, heterozygous kidneys were 25% smaller than wild-type kidneys (wild-type, 114.75 +/- 16.46 mm3; heterozygous, 87.11 +/- 21.84 mm3, P < 0.001) and contained approximately 30% fewer nephrons (wild-type, 11886 +/- 1277; heterozygous, 8573 +/- 2240, P < 0.01). In addition, the absolute ureteric duct volume was significantly reduced in heterozygous mice (P < 0.001). CONCLUSIONS: : These results indicate that the loss of one GDNF allele results in reduced nephron endowment in the adult kidney, presumably as the result of reduced branching morphogenesis of the ureteric bud.
