Abstract
Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apelin / administration & dosage
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Apelin / analogs & derivatives*
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Apelin / blood
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Apelin / metabolism*
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Apelin Receptors / metabolism
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Arginine Vasopressin / adverse effects*
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Arginine Vasopressin / blood
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Blood Glucose / metabolism
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Blood Pressure / drug effects
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Cell Line
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Colforsin / pharmacology
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Cyclic AMP / biosynthesis
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Deamino Arginine Vasopressin / pharmacology
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Disease Models, Animal
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Diuresis* / drug effects
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Electrolytes / blood
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Half-Life
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Hyponatremia / blood
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Hyponatremia / pathology*
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Hyponatremia / physiopathology*
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Hyponatremia / urine
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Kidney Tubules, Collecting / drug effects
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Kidney Tubules, Collecting / metabolism
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Kidney Tubules, Collecting / physiopathology
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Male
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Mice
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Models, Biological
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Myocardial Contraction / drug effects
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Peptides / chemistry
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Peptides / pharmacology
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Phosphorylation / drug effects
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Rats
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Rats, Sprague-Dawley
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Tolvaptan / pharmacology
Substances
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Apelin
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Apelin Receptors
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Blood Glucose
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Electrolytes
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Peptides
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Arginine Vasopressin
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Colforsin
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Tolvaptan
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Cyclic AMP
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Deamino Arginine Vasopressin