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Renal 11β-hydroxysteroid dehydrogenase activities: Pharmacological inhibition and putative regulators

Thompson, Anna; (1999) Renal 11β-hydroxysteroid dehydrogenase activities: Pharmacological inhibition and putative regulators. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Isoforms of the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD) catalyse the metabolism of glucocorticoids to inactive 11ketosteroids. In the kidney, the NAD+-dependent type 2 isoform of 11βHSD appears to confer aldosterone specificity on the mineralocorticoid receptor (MR). The physiological role for the NADP+-dependent type 1 isoform of 11HSD, expressed in the proximal nephron of the rat, is uncertain. Studies described in this thesis were designed to investigate: (a) the consequences of pharmacological inhibition of 11HSD for renal function, and (b) changes in 11HSD activity in response to dietary manipulations known to alter mineralocorticoid status. Intravenous infusion of carbenoxolone (CBX; 6mg/hr) inhibited both NADP+- and NAD+- dependent 11HSD activities by >90% in the rat kidney. This inhibition was associated with reduced urinary excretion of sodium, although potassium excretion was unaffected. While sodium transport in the distal tubule was unaffected by CBX infusion, potassium secretion was significantly increased in this nephron segment. In a separate study, the administration of CBX to adrenalectomised rats inhibited NADP+-dependent 11HSD activity by 80% while NAD+-dependent glucocorticoid oxidation was unaffected, suggesting that adrenalectomy impairs the ability of CBX to inhibit renal glucocorticoid metabolism. In the second series of studies, rats were maintained on either high potassium, low potassium or sodium diets, or NH4CI drinking water for 10 days. NADP+-dependent 11HSD activities in renal homogenates were unchanged with any diet, whereas high potassium, low sodium and acidosis were associated with significant decreases in NAD+-dependent glucocorticoid oxidation. Studies of the microdissected nephron demonstrated that dietary potassium loading tended to increase NADP+-dependent glucocorticoid metabolism, but decreased NAD+-dependent 11HSD activity in all nephron segments with the exception of the outer medullary collecting ducts; an important observation since the role of corticosteroids in this nephron segment is ill-defined. The data reported herein suggest important physiological roles for 11βHSD activities in modulating renal electrolyte balance.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Renal 11β-hydroxysteroid dehydrogenase activities: Pharmacological inhibition and putative regulators
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Kidney function
URI: https://discovery.ucl.ac.uk/id/eprint/10107089
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