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5/6th Nephrectomy in Combination with High Salt Diet and Nitric Oxide Synthase Inhibition to Induce Chronic Kidney Disease in the Lewis Rat
Published on: July 3, 2013
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.
Abstract:
Renal allograft donors are at risk of developing hypertension. Here, we hypothesized that this risk is at least in part explained by an enhanced intracellular availability of 11β-hydroxyglucocorticoids due to an increased 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), an intracellular prereceptor activator of biologically inactive 11-ketocorticosteroids in the liver, and/or a diminished 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an inactivator of 11β-hydroxyglucocorticoids in the kidney. To test this hypothesis, uninephrectomized (UNX) (n=9) and sham-operated (n=10) adult Sprague-Dawley rats were investigated. Mean arterial blood pressure and heart rate were measured continuously by telemetry for 6 days in week 5 after UNX. The mRNA of 11β-Hsd1 and 11β-Hsd2 in liver and kidney tissues were assessed by RT-PCR and the 11β-HSD activities were directly quantified in their corresponding tissues by determining the ratios of (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THB+5α-THB)/THA) and of corticosterone/dehydrocorticosterone (B/A) by gas chromatography-mass spectrometry. The apparent total body activities of 11β-HSD1 and 11β-HSD2 were estimated using the urinary and plasma ratios of (THB+5α-THB)/THA and B/A. Mean arterial blood pressure was increased after UNX when compared with sham operation. Hepatic mRNA content of 11β-Hsd1 and hepatic, plasma, and urinary ratios of (THB+5α-THB)/THA were decreased after UNX, indicating diminished access of glucocorticoids to its receptors. In renal tissue, 11β-Hsd2 mRNA was reduced and B/A ratios measured in kidney, plasma, and urine were increased, indicating reduced 11β-HSD2 activity and enhanced access of glucocorticoids to mineralocorticoid receptors. Both 11β-HSD1 and 11β-HSD2 are downregulated after UNX in rats, a constellation considered to induce hypertension.
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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