Changes in 11 -hydroxysteroid dehydrogenase type 2 expression in a low-protein rat model of intrauterine growth restriction

Abstract

Intrauterine growth restriction (IUGR) is associated with systemic hypertension of the offspring later in life. The exact mechanisms are still incompletely understood. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) in the distal renal tubule protects the mineralocorticoid receptor from cortisol. As we did not find a suppression of 11β-HSD2 in total kidney of IUGR animals, our objective was to investigate whether a suppression of 11β-HSD2 could be detected on a more sophisticated level such as in situ protein and gene expression of 11β-HSD2 in mildly hypertensive IUGR offspring. IUGR rats after maternal low-protein diet (n = 17) were compared with controls (n = 18). At 70 and 120 days of age, in situ distribution of 11β-HSD2 gene and protein expression was investigated by RT-PCR of microdissected tubules and immunohistochemistry. For in situ localization studies, double staining for 11β-HSD2 and calbindin was used. Serum levels of corticosterone and dehydrocorticosterone were measured by tandem mass spectrometry. In IUGR rats, intra-arterial blood pressure significantly increased at Day 120 of life. Serum corticosterone/dehydrocorticosterone ratios and 11β-HSD2 mRNA in total kidney were not altered in IUGR animals. However, 11β-HSD2 mRNA concentration was significantly lower in microdissected tubuli of IUGR animals (Day 120: 0.18 ± 0.14 vs 1.00 ± 0.32 rel. units in controls; P < 0.05). In IUGR animals, immunostaining scores for 11β-HSD2 were significantly lower than in controls (P < 0.05). Double staining with calbindin showed lower expression of 11β-HSD2 in distal segments of the distal tubule. Our data indicate lower gene and protein expression of the pre-receptor enzyme 11β-HSD2 in IUGR animals when looking at specific renal compartments, but not in total kidney extracts. Thus, lower 11β-HSD2 as a mechanism for hypertension later in life might be missed without methods for in situ detection.