11β-Hydroxysteroid dehydrogenases: Participation in hormone synthesis and tissue-specific responsiveness to glucocorticoid
The human 11β-hydroxysteroid dehydrogenase type II enzyme: Comparisons with other species and localization to the distal nephron

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Abstract

Effective glucocorticoid inactivation is currently thought to be an indispensable feature of mineralocorticoid target cells. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor. In the kidney it is the NAD dependent high affinity isoform (11β-HSD2) which is thought to endow specificity on the receptor. The recet cloning of the human, sheep and rabbit 11β-HSD2 enzymes permits a comparison of the enzyme from the three species. Human and rabbit enzymes are 87% identical and of similar length, while the human and sheep enzymes have only 75% identity. The last 12 residues in all three species were found to be highly divergent, but most of the ovine dishomology can be accounted for by the deletion of a single nucleotide toward the C-terminus of the protein resulting in a shift in reading frame generating a protein 27 residues longer than the human isoform. Numerous other deletions were also observed in this region of the sheep cDNA sequence. Furthermore, the rabbit cDNA also displayed a large degree of dishomology with the human sequence a short distance downstream from the termination codon. Conserved overlapping cytoplasmic translocation signals were observed in all three species, suggesting a topology whereby the enzyme is anchored into the endoplasmic reticulum by multiple hydrophobic regions in the N-terminus and the bulk of the 11β-HSD2 peptide is sited in the cytoplasm. A polyclonal antibody generated against the C-terminus of human 11β-HSD2 was used to localize the enzyme within the kidney. A high level of immunoreactivity was observed in distal tubules and collecting ducts, localizing the enzyme to the same part of the nephron as the mineralocorticoid receptor. Moderate levels of staining were also seen in vascular smooth muscle cells. These results support the notion that 11β-HSD2 is an autocrine protector of the mineralocorticoid receptor and that it plays an important role in cardiovascular homeostatic mechanisms.

References (36)

  • Z.S. Krozowski et al.

    Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity

  • A. Naray-Fejes-Toth et al.

    11 beta-Hydroxysteroid dehydrogenase activity in the renal target cells of aldosterone

    Endocrinology

    (1991)
  • S. Ulick et al.

    Defective ring-A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess

    J. Clin. Endocr. Metab.

    (1992)
  • D.J. Morris et al.

    Detection of glycyrrhetinic acid-like factors (GALFs) in human urine

    Hypertension

    (1992)
  • B.R. Walker et al.

    Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase in hypertension

    J. Clin. Endocr. Metab.

    (1995)
  • W.R. Mercer et al.

    Localization of an 11 beta hydroxysteroid dehydrogenase activity to the distal nephron

    Evidence for the existence of two species of dehydrogenase in the rat kidney

    Endocrinology

    (1992)
  • B.R. Walker et al.

    Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase

    Endocrinology

    (1992)
  • E. Rusvai et al.

    A new isoform of 11-beta-hydroxysteroid dehydrogenase in aldosterone target cells

    J. Biol. Chem.

    (1993)
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