Fetal dexamethasone exposure accelerates development of renal function: relationship to dose, cell differentiation and growth inhibition.
Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. Nevertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. The current study examined this apparent paradox in the developing rat kidney, using doses of dexamethasone that span the threshold for growth impairment: 0.05 or 0.2 mg/kg given on gestational days 17, 18 and 19. At the lower dose, which did not significantly retard body growth, the postnatal development of tubular reabsorptive capabilities for sodium, potassium, osmotic particles, water and urea was accelerated. These effects were less notable at the higher dose, which caused initial body growth impairment. The selectivity toward promotion of tubular function was evidenced by the absence of effect of either dose of dexamethasone on development of glomerular filtration rate. Because of the wide spectrum of dexamethasone's effects on tubular function, we also assessed fetal kidney adenylate cyclase as a means of detecting altered cell differentiation in the prenatal period during which dexamethasone was given. Either glucocorticoid dose increased the total adenylate cyclase catalytic activity (assessed with forskolin). Thus, the net effect of fetal dexamethasone exposure on development of renal excretory capabilities probably represents the summation of promoted cell differentiation and slowed development consequent to growth retardation. At low dose levels, the former effect predominates, leading to enhanced functional development, whereas higher doses that interfere with general growth and development can offset the direct promotional effect.
Slotkin
T A
TA
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Seidler
F J
FJ
Kavlock
R J
RJ
Gray
J A
JA
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D005333:Fetus / Q000187:drug effects*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000196:embryology*; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000652:urine; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine; D014508:Urea / Q000652:urine
D003907:Dexamethasone; D014508:Urea; D012964:Sodium; D000262:Adenylyl Cyclases; D011188:Potassium