RETINOIC ACID MANIPULATION OF METANEPHROGENESIS IN C57BL/6J MICE: In Utero & Ex Utero. † 2170

The role of glucocorticoids in production of experimental polycystic kidney disease is well known and recently we have shown ameliorating effects on experimental PKD by thyroid hormone. Retinoic acid (RA) receptors are part of the steroid-thyroid-retinoid receptor superfamily and here we report our investigation of the effect of RA on mouse metanephrogenesis. We found that RA given to pregnant C57BL/6J mice (20mg/kg or 40mg/kg s.c.) on one day between the 5^th and 19^th days of gestation profoundly affected the density of glomeruli (number per standardized high power microscopic field) and the state of glomerular maturation in offspring killed on the day of birth(n₂₀=112; n₄₀=85). In both dose groups, comparison of densities over days of treatment showed a significant quadratic (parabolic) trend with peak values at gestational treatment days 14 and 12 respectively.(P₂₀<0.0001; P₄₀<0.019)*. In addition, there were individual significant density increases, compared with untreated controls, in mice from dams treated on peak-value days, and significant decreases for treatment prior to day 7. Maturation, assessed by comparing the proportions of glomeruli in three contiguous, easily identifiable stages of maturation (“early”, “intermediate” and “mature”), was also affected by RA administration to the dams. Predominantly progression of intermediate to mature forms was enhanced in response to treatment on gestational days 10,16 and 18 for the 20mg/kg group and on days 11 and 14 for the 40 mg/kg group (P₂₀ values<0.042; P₄₀values<0.028). There was no demonstrable correlation between increases in density and increases in maturation, suggesting that RA has independent effects on induction of ureteric budding/glomerular formation and subsequent glomerular/nephron maturation. Kidneys from 5 day old mice, treated with RA on the day of birth, also showed increased glomerular density with 5 day old controls (P<.0001). Glomerular maturation was also enhanced (P<.040), but in contrast to the embryonic experiment, advancement was confined to maturation of early forms to intermediate forms.