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

Publikation: Bidrag til tidsskriftKonferenceabstrakt i tidsskriftForskningpeer review

Abstrakt

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.
OriginalsprogEngelsk
ArtikelnummerPP.28.10
TidsskriftJournal of Hypertension. Supplement
Vol/bind33
Udgave nummere-Supplement 1
Sider (fra-til)e376
Antal sider1
ISSN0263-6352
DOI
StatusUdgivet - jun. 2015
Begivenhed25th European Meeting on Hypertension and Cardiovascular Protection - Milano, Italien
Varighed: 12. jun. 201515. jun. 2015

Konference

Konference25th European Meeting on Hypertension and Cardiovascular Protection
Land/OmrådeItalien
ByMilano
Periode12/06/201515/06/2015

Emneord

  • *urine *injury *tissues *European *hypertension *protection human patient membrane kidney rat plasma kidney parenchyma nephrotic syndrome nephrectomy urinalysis immunoblotting drug therapy homogenate proteinuria resistant hypertension limit of detection diabetic patient non insulin dependent diabetes mellitus antihypertensive therapy enzyme linked immunosorbent assay albuminuria apical membrane infusion filtration glomerular filtration barrier wild type mouse salt intake *aldosterone *mineralocorticoid receptor *prostasin spironolactone placebo puromycin protein aldosterone antagonist receptor blocking agent albumin mineralocorticoid antagonist epithelial sodium channel mineralocorticoid creatinine aldosterone synthase serine proteinase

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