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

Buhl, Kristian Bergholt; Oxlund, Christina Stolzenburg; Friis, Ulla Glenert; Svenningsen, Per; Bistrup, Claus; Jacobsen, I.A.; Jensen, Boye L.

doi:10.1097/hjh.0000000000000216

Cited by 46 publications

(54 citation statements)

References 31 publications

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“…Because of the high collinearity between proteinuria and urinary plasminogen as well as plasmin excretion, these parameters could replace each other in multivariable models and could not be separated by using more sophisticated statistical approaches. Other studies in the field, such as the ones by Buhl et al (5,19), which showed an activating effect of protein-rich urine on ENaC activity in vitro, were also associative. Nevertheless, the data provide strong evidence that proteinuria exerts a strong influence on hypervolemia in a continuous relationship.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the data provide strong evidence that proteinuria exerts a strong influence on hypervolemia in a continuous relationship. Thus far, studies on plasminuria have concentrated on a limited number of patients with single-disease etiologies (preeclampsia [5] or diabetes mellitus [18,19]). The results of this large study were derived from an unselected CKD cohort with different etiologies, making the results highly generalizable.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmin-induced ENaC activation and sodium retention may occur in patients with preeclampsia (5) and diabetic patients who are proteinuric (18,19). Recently, immunohistochemical studies in human nephrectomy specimens indicated that the g-subunit of ENaC was processed proteolytically exclusively in patients with proteinuria (20).…”

Section: Introductionmentioning

confidence: 99%

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Association of Plasminuria with Overhydration in Patients with CKD

Schork

Woern

Kalbacher

et al. 2016

CJASN

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Background and objectives Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria.Design, setting, participants, & measurements In this cross-sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two-electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel.Results Overhydration .5% and overhydration .10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m 2 per 10-fold increase; P,0.001). Urinary excretion of plasmin(ogen) quantified by ELISA correlated strongly with proteinuria (r=0.87) and overhydration (r=0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro. In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria.Conclusions Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the nonnephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Association of Plasminuria with Overhydration in Patients with CKD

Schork

Woern

Kalbacher

et al. 2016

CJASN

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“…Increased γ subunit cleavage has been observed in the setting of nephrotic syndrome 54 . Urinary plasminogen has been found in a growing number of disease processes associated with glomerular proteinuria 31,32,55–58 . Plasminogen can be converted to its active form, plasmin, by urokinase in the tubular lumen 31,32,59–61 .…”

Section: Enac Activation In Nephrotic Syndromementioning

confidence: 99%

“…Buhl and co-workers found that in diabetic patients with resistant hypertension, microalbuminuria is associated with sufficient plasmin to activate ENaC in cultured cells 58 . Thus, even at low levels, proteases filtered by leaky glomeruli may contribute to hypertension.…”

Section: Enac Activation In Nephrotic Syndromementioning

confidence: 99%

Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension

Ray

Rondon‐Berrios

Boyd

et al. 2015

Advances in Chronic Kidney Disease

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Sodium retention is a major clinical feature of nephrotic syndrome. The mechanisms responsible for sodium retention in this setting have been a subject of debate for years. Excessive sodium retention occurs in some individuals with nephrotic syndrome in the absence of activation of the renin-angiotensin-aldosterone system, suggesting an intrinsic defect in sodium excretion by the kidney. Recent studies have provided new insights regarding mechanisms by which sodium transporters are activated by factors present in nephrotic urine. These mechanisms likely have a role in the development of hypertension in nephrotic syndrome, where hypertension may be difficult to control, and provide new therapeutic options for the management of blood pressure and edema in the setting of nephrotic syndrome.

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Epithelial Na ⁺ Channels Function as Extracellular Sensors

Kashlan,

Wang,

Sheng

et al. 2024

Comprehensive Physiology

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The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407‐5447, 2024.

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

Abstract: 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.

Cited by 46 publications

References 31 publications

Association of Plasminuria with Overhydration in Patients with CKD

Association of Plasminuria with Overhydration in Patients with CKD

Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension

Epithelial Na ⁺ Channels Function as Extracellular Sensors

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

Abstract: 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.

Cited by 46 publications

References 31 publications

Association of Plasminuria with Overhydration in Patients with CKD

Association of Plasminuria with Overhydration in Patients with CKD

Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension

Epithelial Na + Channels Function as Extracellular Sensors

Contact Info

Product

Resources

About

Epithelial Na ⁺ Channels Function as Extracellular Sensors