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Plasmin in urine from patients with type 2 diabetes and treatment-resistant hypertension activates ENaC in vitro

Buhl, Kristian B.a; Oxlund, Christina S.b; Friis, Ulla G.a; Svenningsen, Pera; Bistrup, Clausc; Jacobsen, Ib A.b; Jensen, Boye L.a

Journal of Hypertension:
doi: 10.1097/HJH.0000000000000216
ORIGINAL PAPERS: Kidney
Abstract

Background: Aberrant filtration of plasminogen from plasma and subsequent activation to plasmin in the urinary space may activate proteolytically the epithelial sodium channel, ENaC. In conditions with chronic albuminuria, this may cause hypertension. It was hypothesized that patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension excrete plasmin(ogen) in urine in proportion to albumin and that plasmin confers to urine the ability to activate ENaC.

Method: Patients (n = 113) with T2DM and resistant hypertension, defined as systolic blood pressure (SBP) more than 130 mmHg and/or diastolic blood pressure (DBP) more than 80 mmHg despite use of at least three drugs with one diuretic and one renin–angiotensin system inhibitor, were included. Urine was analyzed for albumin, creatinine, plasmin(ogen), protease activity, and ability to activate inward current in single collecting duct cells.

Results: Mean ambulatory SBP/DBP was 143 ± 1/77 ± 0.7 mmHg; HbA1c 7.35%; and eGFR 81.0 ml/min per 1.73 m2 (geometric means). Patients with microalbuminuria (39%) and macroalbuminuria (13%) displayed significantly elevated levels of urinary plasmin(ogen) normalized to urine creatinine compared with patients with normal excretion of albumin (48%). Urinary plasminogen correlated significantly to urine albumin. Western immunoblotting and gelatine zymography confirmed active plasmin in urine samples from patients with microalbuminuria and macroalbuminuria. Single collecting duct cells displayed significantly increased, amiloride-sensitive, inward current when superfused with urine from albuminuric patients compared with patients with normal albumin excretion. Urinary plasminogen/creatinine ratio correlated significantly with 24-h ambulatory blood pressure.

Conclusion: Aberrant presence of plasmin in preurine may inappropriately activate ENaC in patients with type 2 diabetes and microalbuminuria. This may contribute to treatment-resistant hypertension.

Author Information

aDepartment of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark

bDepartment of Endocrinology, Research Unit for Cardiovascular and Metabolic Prevention

cDepartment of Nephrology, Odense University Hospital, Odense, Denmark

Correspondence to Boye L. Jensen, MD, PhD, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, DK-5000, Odense C, Denmark. Tel: +45 6550 3796; fax: +45 6613 3479; e-mail: bljensen@health.sdu.dk

Abbreviations: ACR, albumin-creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ENaC, epithelial sodium channel; HbA1c, glycated hemoglobin; RTHN, treatment-resistant hypertension; T2DM, type 2 diabetes mellitus

Received 31 January, 2014

Revised 19 March, 2014

Accepted 19 March, 2014

The content of the study was presented in abstract form at The American Society for Nephrology meeting, San Diego November 2012.

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