title: Mechanism of alcohol-induced impairment in renal development: Could it be reduced by retinoic acid?
abstract: 1. Prenatal alcohol exposure impairs kidney development, resulting in a reduced nephron number. However, the mechanism through which alcohol acts to disrupt renal development is largely unknown. Retinoic acid (RA) is critically involved in kidney development and it has been proposed that a diminished concentration of RA is a contributing factor to fetal alcohol syndrome. 2. In the present study we proposed that the ethanol-induced inhibition of ureteric branching morphogenesis and glomerular development in the cultured rat kidney would be ameliorated by coculture with exogenous RA and that examining the expression profile of key genes involved in the development of the kidney would provide insights into the potential molecular pathways involved. 3. Whole rat metanephroi cultured in the presence of exogenous RA (10-20 nmol/L) without ethanol appeared larger and had significantly more ureteric branch points, tips and glomeruli than metanephroi cultured in control media. Those cultured in the presence of ethanol alone (0.2%) had 20% fewer ureteric branch points, tips and glomeruli, which was ameliorated by coculture with retinoic acid. 4. Gene expression analysis identified changes in the expression of enzymes involved in the metabolism of alcohol in conjunction with changes in key regulators of kidney development, including cRET. 5. These results demonstrate that the teratogenic effects of alcohol in vitro on kidney development resulting in reduced ureteric branching morphogenesis and glomerular development can be ameliorated through coculture with RA. These results provide the foundation for future research into the mechanism through which alcohol acts to disrupt kidney development.
authors: Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors: Stephen P
authors: SP
authors: Gray
authors: Luise A
authors: LA
authors: Cullen-McEwen
authors: John F
authors: JF
authors: Bertram
authors: Karen M
authors: KM
authors: Moritz
mesh_terms: D000818:Animals; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000187:drug effects*; D009994:Osmolar Concentration; D011247:Pregnancy; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000151:congenital / Q000209:etiology / Q000517:prevention & control; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D013723:Teratogens / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020011:Protective Agents; D047490:Retinoid X Receptor alpha; D013723:Teratogens; D000431:Ethanol; D014212:Tretinoin; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat