Galectin-3 contributes to pathogenesis of IgA nephropathy

Abstract

Abstract IgA nephropathy (IgAN) is the most common type of autoimmune glomerulonephritis that frequently progresses to end-stage renal disease. However, the molecular pathogenesis underlying IgAN remains largely unknown. This study investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis. Two complementary mouse IgAN models, a model induced with TEPC-15 hybridoma using Gal-3 knockout (KO) mice, and a spontaneous IgAN model of “grouped” ddY (gddY) mice were employed. Gal-3 expression increased with disease severity in the glomeruli, peri-glomerular regions, and some renal tubules in both the inducible and spontaneous IgAN models. Gal-3 KO in the TEPC-15 hybridoma-induced IgAN mice significantly improved proteinuria and renal function and reduced severity of renal pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from renal-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved renal inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored renal function and improved renal lesions in passive IgAN mice. These results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Therefore, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this renal disease. Nil