The antioxidant L-Ergothioneine prevents cystine lithiasis in the Slc7a9-/- mouse model of cystinuria
Por:
Mayayo-Vallverdú C, López de Heredia M, Prat E, González L, Espino Guarch M, Vilches C, Muñoz L, Asensi MA, Serra C, Llebaria A, Casado-Rio M, Artuch-Iriberri R, Garrabou G, Garcia-Roves PM, Pallardó FV and Nunes V
Publicada:
1 ago 2023
Ahead of Print:
1 jul 2023
Resumen:
The high recurrence rate of cystine lithiasis observed in cystinuria patients highlights the need for new therapeutic options to address this chronic disease. There is growing evidence of an antioxidant defect in cystinuria, which has led to test antioxidant molecules as new therapeutic approaches. In this study, the antioxidant L- Ergothioneine was evaluated, at two different doses, as a preventive and long-term treatment for cystinuria in the Slc7a9-/- mouse model. L-Ergothioneine treatments decreased the rate of stone formation by more than 60% and delayed its onset in those mice that still developed calculi. Although there were no differences in metabolic parameters or urinary cystine concentration between control and treated mice, cystine solubility was increased by 50% in the urines of treated mice. We also demonstrate that L-Ergothioneine needs to be internalized by its transporter OCTN1 (Slc22a4) to be effective, as when administrated to the double mutant Slc7a9-/-Slc22a4-/- mouse model, no effect on the lithiasis phenotype was observed. In kidneys, we detected a decrease in GSH levels and an impairment of maximal mitochondrial respiratory capacity in cystinuric mice that L-Ergothioneine treatment was able to restore. Thus, L-Ergothioneine administration prevented cystine lithiasis in the Slc7a9-/- mouse model by increasing urinary cystine solubility and recovered renal GSH metabolism and mitochondrial function. These results support the need for clinical trials to test L-Ergothioneine as a new treatment for cystinuria.
Filiaciones:
Mayayo-Vallverdú C:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Genetics Section, Physiological Sciences Department, Health Sciences and Medicine Faculty, University of Barcelona, Barcelona, Spain
López de Heredia M:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Prat E:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Genetics Section, Physiological Sciences Department, Health Sciences and Medicine Faculty, University of Barcelona, Barcelona, Spain
González L:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Espino Guarch M:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Immunology Department, Sidra Medicine, Doha, Qatar
Vilches C:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Institut de Ciències Fotòniques (ICFO), The Barcelona Institute of Science and Technology, 08860, Castelldefels, Barcelona, Spain
Muñoz L:
SIMChem, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
Asensi MA:
Departamento de Fisiología. Universidad de Valencia-INCLIVA, Valencia, Spain
Serra C:
SIMChem, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
Llebaria A:
SIMChem, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
Casado-Rio M:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Artuch-Iriberri R:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Garrabou G:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Muscle Research and Mitochondrial Function Laboratory, Cellex-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Internal Medicine Department-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
Garcia-Roves PM:
Department of Physiological Sciences, School of Medicine and Health Sciences, Nutrition, Metabolism and Gene therapy Group Diabetes and Metabolism Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
Pallardó FV:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) -CB06/07/0069 - CB06/07/0061 - CB06/07/0073 - CB06/07/1002 - Instituto de Salud Carlos III, Madrid, Spain
Departamento de Fisiología. Universidad de Valencia-INCLIVA, Valencia, Spain
Nunes V:
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Genetics Section, Physiological Sciences Department, Health Sciences and Medicine Faculty, University of Barcelona, Barcelona, Spain
Green Submitted, gold
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