Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Abstract

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

• Authors: Tatiana Lobry, Roy Miller, Nathalie Nevo, Celine J Rocca, Jinzhong Zhang, Sergio D Catz, Fiona Moore, Lucie Thomas, Daniel Pouly, Anne Bailleux, Ida Chiara Guerrera, Marie-Claire Gubler, Wai W Cheung, Robert H Mak, Tristan Montier, Corinne Antignac, Stephanie Cherqui
• Journal: Kidney international (Kidney Int) Vol. 96 Issue 2 Pg. 350-362 (08 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 30928021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acid Transport Systems, Neutral
• Ccl2 protein, mouse
• Chemokine CCL2
• Galectin 3
• Lgals3 protein, mouse
• cystinosin protein, mouse
• Cystine

Topics

• Amino Acid Transport Systems, Neutral (genetics, metabolism)
• Animals
• Chemokine CCL2 (immunology, metabolism)
• Cystine (metabolism)
• Cystinosis (complications, immunology, metabolism, pathology)
• Disease Models, Animal
• Disease Progression
• Fanconi Syndrome (immunology, metabolism, pathology)
• Female
• Galectin 3 (genetics, metabolism)
• Humans
• Inflammation (immunology, metabolism, pathology)
• Kidney Tubules, Proximal (immunology, pathology)
• Lysosomes (metabolism)
• Macrophages (immunology)
• Male
• Mice
• Mice, Knockout
• Monocytes (immunology)
• Proteolysis