The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.

流感病毒神经氨酸酶的功能已得到充分证明，但哺乳动物神经氨酸酶的功能仍鲜为人知。在这里，我们描述了神经氨酸酶 1 (NEU1) 在单侧输尿管梗阻 (UUO) 和叶酸 (FA) 诱导的肾纤维化小鼠模型中的作用。我们发现 NEU1 在患者和小鼠的纤维化肾脏中显着上调。在功能上，肾小管上皮细胞特异性 NEU1 敲除可抑制小鼠上皮-间充质转化、炎性细胞因子产生和胶原蛋白沉积。相反，NEU1 过表达会加剧进行性肾纤维化。从机制上讲，NEU1 在 160-200aa 区域与 TGFβ I 型受体 ALK5 相互作用并稳定 ALK5，从而导致 SMAD2/3 激活。丹酚酸B，丹参的成分, 被发现与 NEU1 强烈结合，并以 NEU1 依赖性方式有效地保护小鼠免受肾纤维化。总的来说，这项研究描述了 NEU1 在肾纤维化中的促进作用，并提出了靶向 NEU1 治疗肾脏疾病的潜在途径。