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

中文翻译：

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Galectin-3 参与 IgA 肾病的发病机制


IgA 肾病 (IgAN) 是最常见的肾小球肾炎类型，经常进展为肾衰竭。然而，IgAN 的分子发病机制仍然很大程度上未知。在这里，我们研究了半乳糖苷结合蛋白半乳糖凝集素 3 (Gal-3) 在 IgAN 发病机制中的作用，结果表明 IgAN 患者肾脏的 Gal-3 表达显着增强。在两种 TEPC-15 杂交瘤衍生的 IgA 诱导的、被动的和自发的“分组”ddY IgAN 模型中，随着肾小球、肾小球周围区域和一些肾小管中疾病严重程度的增加，Gal-3 表达明显增加。被动 IgAN 模型中的 Gal-3 敲除 (KO) 显着改善了蛋白尿、肾功能并降低了肾脏病理的严重程度，包括中性粒细胞浸润和肾引流淋巴结中 Th17 细胞的分化减少，尽管调节性 T 细胞的百分比有所增加。 Gal-3 KO 还抑制 NLRP3 炎症小体，但它增强自噬并改善肾脏炎症和纤维化。此外，给予 6-脱-O-硫酸化、N-乙酰化低分子量肝素（一种竞争性 Gal-3 结合抑制剂）可恢复被动 IgAN 小鼠的肾功能并改善肾脏病变。因此，我们的结果表明，Gal-3 通过激活 NLRP3 炎性体并促进 Th17 细胞分化，在 IgAN 发病机制中发挥着重要作用。因此，靶向 Gal-3 的作用可能代表治疗这种肾脏疾病的新治疗策略。