Aldosterone-mineralocorticoid receptor promotes urine prostasin through glomerular barrier injury and not tissue abundance

Christina Stolzenburg Oxlund, B. Kurt, I. Schwarzensteiner, M. Hansen, Mette Stæhr, P. Svenningsen, A. Toft, G. Henrichs, C. Bistrup, I. Jacobsen, B. L. Jensen

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Abstract

Objective: Low salt intake or infusion with the mineralocorticoid hormone aldosterone increases the abundance of proteolytically activated gamma ENaC in rat kidney. Prostasin is a serine proteinase GPI-anchored to the apical membrane of renal principal cells. It was hypothesized that the aldosterone- mineralocorticoid receptor (MR) pathway maintains prostasin abundance in human kidney. Design and method: Urine and plasma prostasin was measured by ELISA in urine and plasma from a cohort of type-2 diabetes patients (n = 112) with treatment resistant hypertension before and after intervention with placebo or the mineralocorticoid antagonist spironolactone. Western immunoblotting of creatinine-normalized urine samples was performed from placebo and spironolactone treated patients with and without albuminuria. Tissue prostasin was measured in membranes from human nephrectomy recieving either ACE-i/ANGII or no antihypertensive treatment prior to operation. Urine and tissue prostasin was measured in puromycin-induced nephrotic syndrome rats. Results: Plasma prostasin concentration increased significantly with spironolactone but was not changed with placebo. Urine prostasin concentration was below detection limit and in concentrated urine samples no difference was detected between placebo and spironolactone group by ELISA while western immunoblotting showed correlation of urine prostasin with albumin and a reduction in both with spironolactone. Patients with proteinuria displayed elevated u-prostasin compared to control. Puromycin-induced nephrotic syndrome in rats was associated with significant increase in u-prostasin while kidney tissue prostasin protein abundance was not changed. Prostasin protein abundance was similar in membranes from human nephrectomy homogenate from patients treated preoperatively with ACE-i/ANGII receptor blocker compared to patients given no medication; in kidney membranes from adrenalectomized rats compared to control and in kidney and colon membranes from aldosterone synthase-/- mice compared to wild type littermates. Conclusions: Kidney tissue prostasin is not regulated by aldosterone whereas in conditions with glomerular filtration barrier injury, there is aberrant filtration of prostasin that is sensitive to aldosterone antagonists. Prostasin is not a relevant direct target for aldosterone antagonists.
Original languageEnglish
Article numberPP.28.10
JournalJournal of Hypertension. Supplement
Volume33
Issue numbere-Supplement 1
Pages (from-to)e376
Number of pages1
ISSN0263-6352
DOIs
Publication statusPublished - Jun 2015
Event25th European Meeting on Hypertension and Cardiovascular Protection - Milano, Italy
Duration: 12. Jun 201515. Jun 2015

Conference

Conference25th European Meeting on Hypertension and Cardiovascular Protection
Country/TerritoryItaly
CityMilano
Period12/06/201515/06/2015

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