Article (Scientific journals)
Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.
Rega, L R; Janssens, V; Graversen, J H et al.
2023In Scientific Reports, 13 (1), p. 17276
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Keywords :
Multidisciplinary
Abstract :
[en] Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.
Disciplines :
Urology & nephrology
Author, co-author :
Rega, L R;  Nephrology Research Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Janssens, V;  Cell Biology Unit, de Duve Institute and Louvain University Medical School, Brussels, Belgium
Graversen, J H;  Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
Moestrup, S K;  Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
Cairoli, S;  Division of Metabolic Diseases and Drug Biology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Goffredo, B M;  Division of Metabolic Diseases and Drug Biology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Nevo, N;  Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France
Courtoy, G E;  Imaging Platform (2IP), Institut de Recherche Expérimentale et Clinique, Louvain University Medical School, Brussels, Belgium
Jouret, François  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
Antignac, C;  Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France
Emma, F;  Nephrology Research Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Pierreux, C E;  Cell Biology Unit, de Duve Institute and Louvain University Medical School, Brussels, Belgium. christophe.pierreux@uclouvain.be
Courtoy, P J;  Cell Biology Unit, de Duve Institute and Louvain University Medical School, Brussels, Belgium. pierre.courtoy@uclouvain.be
More authors (3 more) Less
Language :
English
Title :
Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.
Publication date :
12 October 2023
Journal title :
Scientific Reports
eISSN :
2045-2322
Publisher :
Springer Science and Business Media LLC, England
Volume :
13
Issue :
1
Pages :
17276
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Cystinosis Research Foundation [US-CA]
DNRF - Danish National Research Foundation [DK]
Fondation Léon Fredericq [BE]
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since 13 October 2023

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