Urokinase (u‐PA) is produced by collecting duct principal cells and is post‐transcriptionally regulated by SV40 large‐T, arginine vasopressin, and epidermal growth factor

Piedagnel, Rémi; Tiger, Yoann; Lelongt, Brigitte; Ronco, Pierre

doi:10.1002/jcp.20485

Cited by 15 publications

(16 citation statements)

References 59 publications

(64 reference statements)

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“…A candidate for renal tubular plasminogen activation is uPA. 30,31 In agreement with previous findings, 30 we found uPA expressed at the apical surface of CCD. Western blotting confirmed expression of uPA in rat kidney cortex.…”

Section: Discussionsupporting

confidence: 93%

Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Svenningsen

Bistrup²,

Friis³

et al. 2009

Journal of the American Society of Nephrology

228

366

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Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC ␥ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.

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Section: Discussionsupporting

confidence: 93%

Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Svenningsen

Bistrup²,

Friis³

et al. 2009

Journal of the American Society of Nephrology

228

366

View full text Add to dashboard Cite

show abstract

“…One protease that has received interest in this context is plasmin, a protease cleaved from plasminogen by tissue plasminogen activator (TPA) and urokinase/u-PA. Plasmin is usually involved in fibrinolysis, providing a rationale for the use of TPA to reduce or prevent clot formation. However, levels of plasmin and plasminogen are elevated in the urine of nephrotic patients (395), while TPA and urokinase are both expressed in the kidney (233,308). Recent evidence has shown that plasmin present in nephrotic urine can cleave ␥ENaC, thereby activating the channel and increasing sodium absorption (298, 299, 374).…”

Section: Other Roles For Enac In Vascular-cardio-renal Diseasementioning

confidence: 99%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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“…The presence of urokinase within the tubular lumen of the nephron facilitates the processing of filtered plasminogen to an active form. 8,11,12 Plasmin joins a growing list of proteases that cleave the ␥ subunit at sites distal to the furin cleavage site and activates ENaC in association with release of an inhibitory tract. 3,5,13 These observations provide new insights regarding a mechanism for renal Na ϩ retention in nephrotic syndrome.…”

Section: Plasmin and Sodium Retention In Nephrotic Syndromementioning

confidence: 99%

“…This phosphatonin carries out some effects independent of phosphorus, such as its inhibitory effect on parathyroid hormone synthesis, 9 but, so far, most of the biologic actions of FGF-23, including its recently described association with mortality, 10 seem to be highly interdependent and related to phosphorus, parathyroid hormone, and vitamin D metabolism. 11,12 In this issue of JASN, Isakova et al 13 investigate in a prospective cohort of incident hemodialysis patients the hypothesis that therapy with any type of phosphate binder versus no phosphate binder offers survival benefit. To mimic a randomized trial, they used an interesting approach, performing multivariate-adjusted "intention to treat" analysis and multivariate-adjusted "as treated" analysis in which the analyses started at the time the therapy began.…”

Section: Disclosuresmentioning

confidence: 99%