Key result
In 113 patients with type 2 diabetes and resistant hypertension, those with microalbuminuria (39%) or macroalbuminuria (13%) had significantly elevated urinary plasmin(ogen) that activated ENaC.
Cross-Sectional (n=113)
Urinary plasmin is elevated in diabetic patients with albuminuria and resistant hypertension, and can activate ENaC in vitro, suggesting a mechanism for sodium retention and hypertension in this population.
Elevated urinary plasmin may promote ENaC activation in albuminuric diabetes; hypothesis-generating for plasmin-targeted interventions in resistant hypertension.
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 m (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.
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Buhl et al. (2014) conducted a cross-sectional in type 2 diabetes mellitus and treatment-resistant hypertension (n=113). Albuminuria vs. Normal albumin excretion was evaluated on Urinary plasmin(ogen) levels and ENaC activation. In 113 patients with type 2 diabetes and resistant hypertension, those with microalbuminuria (39%) or macroalbuminuria (13%) had significantly elevated urinary plasmin(ogen) that activated ENaC.
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