Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel

Henrik Andersen; Maria Hoj Hansen; Kristian B. Buhl; Mette Staehr; Ulla G. Friis; Camilla Enggaard; Shanya Supramaniyam; Ida K. Lund; Per Svenningsen; Pernille B. L. Hansen; Boye L. Jensen

doi:10.1161/JAHA.120.016387

Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel

Henrik Andersen, Maria Hoj Hansen, Kristian B. Buhl, Mette Staehr, Ulla G. Friis, Camilla Enggaard, Shanya Supramaniyam, Ida K. Lund, Per Svenningsen, Pernille B. L. Hansen, Boye L. Jensen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

12 Citationer (Scopus)

12 Downloads (Pure)

Abstract

Background

Diabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus.

Methods and Results

Male plasminogen knockout (plasminogen-deficient [Plg(-/-)]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg(-/-) mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg(-/-) control mice, ANGII did not change blood pressure in diabetic Plg(-/-) mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg(-/-) mice with or without diabetes mellitus. Full-length gamma-ENaC and alpha-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa gamma-ENaC cleavage product was increased in diabetic versus nondiabetic mice.

Conclusions

Plasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.

Originalsprog	Engelsk
Artikelnummer	016387
Tidsskrift	Journal of the American Heart Association
Vol/bind	9
Udgave nummer	23
Sider (fra-til)	1-36
Antal sider	36
ISSN	2047-9980
DOI	https://doi.org/10.1161/JAHA.120.016387
Status	Udgivet - 2020

Adgang til dokumentet

10.1161/JAHA.120.016387Licens: CC BY-NC-ND

JAHA.120.016387Forlagets udgivne version, 2,39 MBLicens: CC BY-NC-ND

Citationsformater

Andersen, H., Hansen, M. H., Buhl, K. B., Staehr, M., Friis, U. G., Enggaard, C., Supramaniyam, S., Lund, I. K., Svenningsen, P., Hansen, P. B. L., & Jensen, B. L. (2020). Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel. Journal of the American Heart Association, 9(23), 1-36. [016387]. https://doi.org/10.1161/JAHA.120.016387

Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel. / Andersen, Henrik; Hansen, Maria Hoj; Buhl, Kristian B.; Staehr, Mette; Friis, Ulla G.; Enggaard, Camilla; Supramaniyam, Shanya; Lund, Ida K.; Svenningsen, Per; Hansen, Pernille B. L.; Jensen, Boye L.

I: Journal of the American Heart Association, Bind 9, Nr. 23, 016387, 2020, s. 1-36.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Andersen, H, Hansen, MH, Buhl, KB, Staehr, M, Friis, UG, Enggaard, C, Supramaniyam, S, Lund, IK, Svenningsen, P, Hansen, PBL & Jensen, BL 2020, 'Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel', Journal of the American Heart Association, bind 9, nr. 23, 016387, s. 1-36. https://doi.org/10.1161/JAHA.120.016387

Andersen, Henrik ; Hansen, Maria Hoj ; Buhl, Kristian B. ; Staehr, Mette ; Friis, Ulla G. ; Enggaard, Camilla ; Supramaniyam, Shanya ; Lund, Ida K. ; Svenningsen, Per ; Hansen, Pernille B. L. ; Jensen, Boye L. / Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel. I: Journal of the American Heart Association. 2020 ; Bind 9, Nr. 23. s. 1-36.

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title = "Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel",

abstract = "BackgroundDiabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus.Methods and ResultsMale plasminogen knockout (plasminogen-deficient [Plg(-/-)]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg(-/-) mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg(-/-) control mice, ANGII did not change blood pressure in diabetic Plg(-/-) mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg(-/-) mice with or without diabetes mellitus. Full-length gamma-ENaC and alpha-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa gamma-ENaC cleavage product was increased in diabetic versus nondiabetic mice.ConclusionsPlasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.",

keywords = "albuminuria, aldosterone, protease, renin, sodium channels, ARTERIAL-BLOOD PRESSURE, VOLUME EXPANSION, NA+ CHANNELS, ACTIVATION, ENAC, SYSTEM, URINE, NEPHROPATHY, UROKINASE, SALT",

author = "Henrik Andersen and Hansen, {Maria Hoj} and Buhl, {Kristian B.} and Mette Staehr and Friis, {Ulla G.} and Camilla Enggaard and Shanya Supramaniyam and Lund, {Ida K.} and Per Svenningsen and Hansen, {Pernille B. L.} and Jensen, {Boye L.}",

year = "2020",

doi = "10.1161/JAHA.120.016387",

language = "English",

volume = "9",

pages = "1--36",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "Wiley-Blackwell",

number = "23",

}

TY - JOUR

T1 - Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel

AU - Andersen, Henrik

AU - Hansen, Maria Hoj

AU - Buhl, Kristian B.

AU - Staehr, Mette

AU - Friis, Ulla G.

AU - Enggaard, Camilla

AU - Supramaniyam, Shanya

AU - Lund, Ida K.

AU - Svenningsen, Per

AU - Hansen, Pernille B. L.

AU - Jensen, Boye L.

PY - 2020

Y1 - 2020

N2 - BackgroundDiabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus.Methods and ResultsMale plasminogen knockout (plasminogen-deficient [Plg(-/-)]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg(-/-) mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg(-/-) control mice, ANGII did not change blood pressure in diabetic Plg(-/-) mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg(-/-) mice with or without diabetes mellitus. Full-length gamma-ENaC and alpha-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa gamma-ENaC cleavage product was increased in diabetic versus nondiabetic mice.ConclusionsPlasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.

AB - BackgroundDiabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus.Methods and ResultsMale plasminogen knockout (plasminogen-deficient [Plg(-/-)]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg(-/-) mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg(-/-) control mice, ANGII did not change blood pressure in diabetic Plg(-/-) mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg(-/-) mice with or without diabetes mellitus. Full-length gamma-ENaC and alpha-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa gamma-ENaC cleavage product was increased in diabetic versus nondiabetic mice.ConclusionsPlasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.

KW - albuminuria

KW - aldosterone

KW - protease

KW - renin

KW - sodium channels

KW - ARTERIAL-BLOOD PRESSURE

KW - VOLUME EXPANSION

KW - NA+ CHANNELS

KW - ACTIVATION

KW - ENAC

KW - SYSTEM

KW - URINE

KW - NEPHROPATHY

KW - UROKINASE

KW - SALT

U2 - 10.1161/JAHA.120.016387

DO - 10.1161/JAHA.120.016387

M3 - Journal article

C2 - 33215566

VL - 9

SP - 1

EP - 36

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 23

M1 - 016387

ER -