Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Autor: Annemiete W.C.M. van der Kemp, Siebe van Genesen, Sjoerd Verkaart, Arjan J. Kwakernaak, Kukiat Tudpor, Joost G. J. Hoenderop, Gerarda Navis, Nadezda V. Kovalevskaya, Sergio Lainez, René J. M. Bindels
Přispěvatelé: Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP)
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
Models
Molecular
Nephrotic Syndrome
Plasmin
PKC Phosphorylation Site
DESENSITIZATION
ACTIVATION
THROMBIN RECEPTOR
CA2+ CHANNEL
Serine
Fibrinolysin
Transcellular
Phosphorylation
CALMODULIN
Kidney Tubules
Distal
Protein Kinase C
Chemistry
Reabsorption
General Medicine
Middle Aged
EPITHELIAL NA+ CHANNELS
Proteinuria
medicine.anatomical_structure
Nephrology
NEPHROCALCINOSIS
medicine.drug
medicine.medical_specialty
CALCIUM-CHANNELS
Molecular Sequence Data
PARATHYROID-HORMONE
TRPV Cation Channels
Internal medicine
medicine
Humans
Receptor
PAR-1
Distal convoluted tubule
Amino Acid Sequence
Calcium Signaling
RNA
Messenger
Nuclear Magnetic Resonance
Biomolecular
Protein kinase C
Urokinase
Base Sequence
IDENTIFICATION
medicine.disease
Membrane transport and intracellular motility Renal disorder [NCMLS 5]
Endocrinology
Basic Research
HEK293 Cells
Calcium
Nephrotic syndrome
Zdroj: Journal of the American Society of Nephrology, 23(11), 1824-1834. AMER SOC NEPHROLOGY
Journal of the American Society of Nephrology, 23, 1824-34
Journal of the American Society of Nephrology, 23, 11, pp. 1824-34
ISSN: 1046-6673
Popis: Item does not contain fulltext Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca(2+) reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca(2+) uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patch-clamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca(2+) uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5.
Databáze: OpenAIRE
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