1. Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis
- Author
-
Lobry, Tatiana, Miller, Roy, Nevo, Nathalie, Rocca, Celine J, Zhang, Jinzhong, Catz, Sergio D, Moore, Fiona, Thomas, Lucie, Pouly, Daniel, Bailleux, Anne, Guerrera, Ida Chiara, Gubler, Marie-Claire, Cheung, Wai W, Mak, Robert H, Montier, Tristan, Antignac, Corinne, and Cherqui, Stephanie
- Subjects
Male ,Kidney Disease ,Amino Acid Transport Systems ,Knockout ,Galectin 3 ,Cystinosis ,Neutral ,Clinical Sciences ,Renal and urogenital ,monocyte chemoattractant protein-1 ,Monocytes ,Mice ,monocyte chemoattractant protein–1 ,galectin-3 ,Animals ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Chemokine CCL2 ,Inflammation ,Animal ,Macrophages ,Proximal ,Urology & Nephrology ,Fanconi Syndrome ,Kidney Tubules ,Disease Models ,Proteolysis ,Disease Progression ,Cystine ,Female ,Lysosomes ,chronic kidney disease - 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.
- Published
- 2019