Ontogeny of 11 beta-hydroxysteroid dehydrogenase in ovine fetal kidney and lung

Abstract

Eleven-beta-hydroxysteroid dehydrogenase (11 beta-HSD) is an enzyme which degrades 11-hydroxycorticosteroids to biologically inactive 11-oxocorticosteroids (cortisone and 11-dehydrocorticosterone). In some tissues, the activity of this enzyme prevents binding of cortisol to mineralocorticoid receptors. The present experiments were designed to test the hypothesis that the fetal kidney contains 11 beta-HSD, that the activity of 11 beta-HSD in fetal kidney increases near term, and that the fetal lung does not contain significant 11 beta-HSD activity. In kidney and lung tissue from 23 fetal sheep ranging in age between 86 and 145 days' gestation, we measured 11 beta-HSD activity. We found significant activity in fetal kidney (14-85% conversion from cortisol to cortisone) but no measurable activity in fetal lung (0-9%). The activity of 11 beta-HSD was significantly related to fetal gestational age (r = 0.76, n = 14). We conclude that 11 beta-HSD activity in the fetal kidney develops as a function of fetal gestational age, and that activity cannot be demonstrated in fetal lung. We speculate 11 beta-HSD in the fetus might function to alter the sensitivity of target organs to glucocorticoids, as well as to mineralocorticoids, and that the absence of activity in the lung allows a high sensitivity of pulmonary tissue to cortisol at the end of gestation.

Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol

“…This finding is consistent with previous observations that showed no alteration in renal 11 -HSD2 mRNA abundance in fetal sheep over this period of late gestation . However, earlier studies have shown an increase in both renal 11 -HSD2 gene expression and activity between 80-100 days and term (Wood & Srun 1995, Langlois et al 1995. Taken together, these observations suggest that renal 11 -HSD2 activity may rise during nephrogenesis which occurs throughout mid to late gestation but is complete by about 130 days of gestation in the sheep (Wintour 1997).…”

“…The 11 -HSD1 isoform is found in a number of adult tissues while 11 -HSD2 is present primarily in aldosterone-sensitive tissues, such as the kidney, colon and salivary glands (White et al 1997, Burton & Waddell 1999. Studies in several species including the sheep have shown a similar distribution of 11 -HSD isoforms in fetal tissues with high 11 -HSD2 expression in the fetal kidneys (Langlois et al 1995, Stewart et al 1995b, Wood & Srun 1995, Brown et al 1996.…”

“…Tissue 11 -HSD2 Tissue 11 -HSD2 activity was measured using the method described by Wood & Srun (1995). Known weights of placenta and renal cortex were homogenized (0·2 g/ml) in ice-cold Krebs-Henseleit buffer containing sodium bicarbonate (pH 7·4).…”

“…Gestational trends in placental 11 -HSD2 gene expression and/or activity have also been observed in sheep, pigs, guinea pigs and humans (Stewart et al 1995a, Klemcke & Christenson 1996, Sampath-Kumar et al 1988. Similarly, there are changes in renal 11 -HSD2 expression and activity between mid and late gestation and in response to hypoxaemia, acidosis and undernutrition in the sheep fetus (Langlois et al 1995, Wood & Srun 1995, Asano et al 1997. In sheep and other species, the fetal adrenal output of glucocorticoids increases towards term and in response to adverse intrauterine conditions, such as undernutrition and hypoxaemia (Fowden & Silver 1995.…”

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

“…In comparison, 11 -HSD type 2 is a unidirectional NAD + -dependent dehydrogenase that converts cortisol to cortisone (Rusvai & Naray-Fejes-Toth 1993). Thus the expression of 11 -HSD isoenzymes and the direction of activity may be important in the local regulation of corticosteroid concentrations within glucocorticoid target tissues (Whorwood et al 1993, Rajan et al 1996 such as liver (Tannin et al 1991, Jamieson et al 1995, lung (Hundertmark et al 1995, Wood & Srun 1995, placenta , adipose tissue (Bujalska et al 1997, Rask et al 2001, gonad (Ricketts et al 1998b) and the central nervous system (Kim et al 1995). In the fetal sheep liver 11 -HSD1 was highly expressed, whereas 11 -HSD2 mRNA and activity were undetectable .…”