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

Return to Grants

Publication Year:
2019
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
PubMed ID:
30928021
Funding Grants:
Public Summary:
Despite treatment, patients still progress to end-stage kidney failure. In this study we showed that absence of cystinosin results in impaired galectin-3 (Gal-3) lysosomal degradation, leading to inflammation and the progression of chronic kidney disease in cystinosis. These findings open new perspectives in potential therapeutic targets that could limit or delay kidney degeneration in patients with cystinosis. As such, antiinflammatory drugs and inhibitors of Gal-3 such as nonsteroidal antiinflammatory drugs or indomethacin may improve the renal pathogenesis in cystinosis.
Scientific 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 beta-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.