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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.