Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood

M Lauterburg1, G Escher, B Dick

  • 1Department of Nephrology and Hypertension, University Hospital Bern, Inselspital, Freiburgstrasse 15, 3010 Bern, Switzerland.

Insights

Uninephrectomy in rats increases blood pressure by downregulating hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzymes, affecting glucocorticoid availability.

Area of Science:

  • Endocrinology
  • Nephrology
  • Cardiovascular Physiology

Background:

  • Renal allograft donors face increased hypertension risk.
  • This risk may stem from altered intracellular glucocorticoid metabolism.
  • Key enzymes involved are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2).

Purpose of the Study:

  • To investigate the role of 11β-HSD1 and 11β-HSD2 in post-uninephrectomy hypertension.
  • To test the hypothesis that altered enzyme activity impacts glucocorticoid availability and blood pressure.

Main Methods:

  • Adult Sprague-Dawley rats underwent uninephrectomy (UNX) or sham surgery.
  • Mean arterial blood pressure and heart rate were monitored via telemetry.
  • mRNA levels of 11β-Hsd1 and 11β-Hsd2 were quantified using RT-PCR.
  • Enzyme activities were assessed by measuring metabolite ratios (e.g., corticosterone/dehydrocorticosterone) in tissues, plasma, and urine using gas chromatography-mass spectrometry.

Main Results:

  • UNX rats exhibited increased mean arterial blood pressure compared to sham-operated rats.
  • Hepatic 11β-HSD1 mRNA and activity (indicated by THB/THA ratios) were decreased post-UNX.
  • Renal 11β-HSD2 mRNA and activity (indicated by B/A ratios) were reduced post-UNX.
  • These changes suggest diminished glucocorticoid access to hepatic receptors and enhanced access to renal mineralocorticoid receptors.

Conclusions:

  • Uninephrectomy in rats leads to the downregulation of both hepatic 11β-HSD1 and renal 11β-HSD2.
  • This dual downregulation is associated with increased blood pressure, suggesting a role in post-nephrectomy hypertension.
  • Altered glucocorticoid metabolism via 11β-HSD enzymes contributes to the hypertensive risk in uninephrectomized individuals.

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