Glucocorticoid metabolism in proximal tubules modulates angiotensin II-induced electrolyte transport.
The hormonal interactions that regulate electrolyte transport in the proximal tubule are complex and incompletely understood. Since endogenous glucocorticoids and angiotensin II each can affect electrolyte transport in this renal segment, we hypothesized that local metabolism of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) might alter the response to angiotensin II. Studies were conducted in cultured origin defective SV-40 transformed immortalized renal proximal tubule cells (IRPTC) derived from weanling Wistar rat kidney. The 11beta-HSD contained in these cells uses NADP+, has an apparent Km for corticosterone of 1.6 microM, but functions only as a dehydrogenase (corticosterone --> 11-dehydro-corticosterone). When mounted in modified Ussing chambers, IRPTC generate a transmembrane current, and angiotensin II (10 pM to 10 microM) increases this sodium-dependent current. Cells incubated with corticosterone (100 nM) and the 11beta-HSD inhibitor carbenoxolone (CBX) (1 microM) for 24 hr and then acutely stimulated with angiotensin (10 nM) show a greater rise in current than do cells exposed to corticosterone alone and stimulated with angiotensin (corticosterone + CBX: 64.2% +/- 20.5% vs. corticosterone: 18.8% +/- 5.9%; P < 0.02 at 180 min)[mean +/- SE percentage above baseline, n = 8/group]. Cells exposed to corticosterone (100 nM) or CBX (1 microM) alone for 24 hr and then stimulated with angiotensin II (10 nM) had responses similar to controls. Thus glucocorticoids can enhance angiotensin II-induced electrolyte transport in proximal tubule epithelial cells when local 11beta-HSD is inhibited.
Brem
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AS
Division of Pediatric Nephrology, Rhode Island Hospital, Providence, Rhode Island 02903, USA. Andrew_Brem@Brown.edu
Bina
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RB
Fitzpatrick
C
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King
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Tang
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Ingelfinger
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JR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D002229:Carbenoxolone / Q000494:pharmacology; D002461:Cell Line, Transformed; D003345:Corticosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D000804:Angiotensin II; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D003345:Corticosterone