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

Research output: Contribution to journalConference abstract in journalResearchpeer-review

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 - 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
CountryItaly
CityMilano
Period12/06/201515/06/2015

Cite this

@article{ca15d030d73e464e9d755edf065948b4,
title = "Aldosterone-mineralocorticoid receptor promotes urine prostasin through glomerular barrier injury and not tissue abundance",
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.",
keywords = "*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",
author = "{Stolzenburg Oxlund}, Christina and B. Kurt and I. Schwarzensteiner and M. Hansen and Mette St{\ae}hr and P. Svenningsen and A. Toft and G. Henrichs and C. Bistrup and I. Jacobsen and Jensen, {B. L.}",
year = "2015",
doi = "10.1097/01.hjh.0000468549.10232.87",
language = "English",
volume = "33",
pages = "e376",
journal = "Journal of Hypertension. Supplement",
issn = "0952-1178",
publisher = "Lippincott Williams & Wilkins, Ltd.",
number = "e-Supplement 1",

}

Aldosterone-mineralocorticoid receptor promotes urine prostasin through glomerular barrier injury and not tissue abundance. / Stolzenburg Oxlund, Christina; Kurt, B.; Schwarzensteiner, I.; Hansen, M.; Stæhr, Mette; Svenningsen, P.; Toft, A.; Henrichs, G.; Bistrup, C.; Jacobsen, I.; Jensen, B. L.

In: Journal of Hypertension. Supplement, Vol. 33, No. e-Supplement 1, PP.28.10, 2015, p. e376.

Research output: Contribution to journalConference abstract in journalResearchpeer-review

TY - ABST

T1 - Aldosterone-mineralocorticoid receptor promotes urine prostasin through glomerular barrier injury and not tissue abundance

AU - Stolzenburg Oxlund, Christina

AU - Kurt, B.

AU - Schwarzensteiner, I.

AU - Hansen, M.

AU - Stæhr, Mette

AU - Svenningsen, P.

AU - Toft, A.

AU - Henrichs, G.

AU - Bistrup, C.

AU - Jacobsen, I.

AU - Jensen, B. L.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - 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 diabeti

U2 - 10.1097/01.hjh.0000468549.10232.87

DO - 10.1097/01.hjh.0000468549.10232.87

M3 - Conference abstract in journal

VL - 33

SP - e376

JO - Journal of Hypertension. Supplement

JF - Journal of Hypertension. Supplement

SN - 0952-1178

IS - e-Supplement 1

M1 - PP.28.10

ER -