Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel.
J Am Heart Assoc
; 9(23): e016387, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-33215566
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 γ-ENaC and α-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa γ-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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasminogênio
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Angiotensina II
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Diabetes Mellitus Tipo 1
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Bloqueadores do Canal de Sódio Epitelial
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Amilorida
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Hipertensão
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article