Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content

L. R. Rega, V. Janssens, J. H. Graversen, S. K. Moestrup, S. Cairoli, B. M. Goffredo, N. Nevo, G. E. Courtoy, F. Jouret, C. Antignac, F. Emma, C. E. Pierreux*, P. J. Courtoy*

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Abstract

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.

OriginalsprogEngelsk
Artikelnummer17276
TidsskriftScientific Reports
Vol/bind13
Antal sider14
ISSN2045-2322
DOI
StatusUdgivet - 12. okt. 2023

Bibliografisk note

Funding Information:
This work was supported by grant CRFF-2019-001A from the Cystinosis Research Foundation (to LRR, CEP & PJC); Danish National Research Foundation under Grant DNRF141 to Center for Functional Genomics and Tissue Plasticity (ATLAS); and Fondation Léon Fredericq, ULiège, Belgium (to FJ). We are grateful to Prof. E.I. Christensen (Aarhus University) for suggesting oral lysine as megalin competitor and to Dr. D. Vertommen (DDUV, UCL-Brussels) for several preliminary tests. The senior authors express admiration to both first authors for responsible handling of the project during severe Covid-19 restrictions.

Funding Information:
This work was supported by grant CRFF-2019-001A from the Cystinosis Research Foundation (to LRR, CEP & PJC); Danish National Research Foundation under Grant DNRF141 to Center for Functional Genomics and Tissue Plasticity (ATLAS); and Fondation Léon Fredericq, ULiège, Belgium (to FJ). We are grateful to Prof. E.I. Christensen (Aarhus University) for suggesting oral lysine as megalin competitor and to Dr. D. Vertommen (DDUV, UCL-Brussels) for several preliminary tests. The senior authors express admiration to both first authors for responsible handling of the project during severe Covid-19 restrictions.

Publisher Copyright:
© 2023, Springer Nature Limited.

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