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靶向神经氨酸酶 4 可减轻小鼠肾脏纤维化。

Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice.

机构信息

School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.

出版信息

Adv Sci (Weinh). 2024 Oct;11(39):e2406936. doi: 10.1002/advs.202406936. Epub 2024 Aug 13.

DOI:10.1002/advs.202406936
PMID:39136142
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11497051/
Abstract

Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial-to-mesenchymal transition, reduces the production of pro-fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4 interacts with Yes-associated protein (YAP) at WW2 domain (231-263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3',4'-Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4-dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

摘要

尽管在治疗方面取得了重大进展，但对于导致肾纤维化的分子因素仍缺乏实质性证据。神经氨酸酶 4（NEU4）是一种从糖缀合物中去除唾液酸的酶，其在慢性进行性纤维化中的作用尚不清楚。本研究发现，NEU4 在叶酸或单侧输尿管梗阻诱导的小鼠纤维化肾脏中表达明显上调，在肾纤维化患者中也观察到这种上调。NEU4 在肾脏中的特异性敲低可减轻上皮间质转化，减少促纤维化细胞因子的产生，并减少雄性小鼠的细胞衰老。相反，NEU4 的过表达会加剧肾纤维化的进展。在机制上，NEU4 与 Yes 相关蛋白（YAP）在 WW2 结构域（231-263aa）相互作用，促进其核易位和靶基因的激活，从而促进肾纤维化。3,5,6,7,8,3',4'-七甲氧基黄酮是一种天然化合物，被鉴定为一种新型 NEU4 抑制剂，可有效依赖 NEU4 保护小鼠免受肾纤维化。综上所述，这些发现表明 NEU4 可能成为治疗肾纤维化的有前途的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/091451cdaf1d/ADVS-11-2406936-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/54d81b92560f/ADVS-11-2406936-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/0a27bab81628/ADVS-11-2406936-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/a681fd19ec6a/ADVS-11-2406936-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/05aa078b5821/ADVS-11-2406936-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/ae17b8573f03/ADVS-11-2406936-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/091451cdaf1d/ADVS-11-2406936-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/54d81b92560f/ADVS-11-2406936-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/19c7483a8869/ADVS-11-2406936-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/0a27bab81628/ADVS-11-2406936-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/1c9bdfda2797/ADVS-11-2406936-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/a681fd19ec6a/ADVS-11-2406936-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/05aa078b5821/ADVS-11-2406936-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/ae17b8573f03/ADVS-11-2406936-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c4c/11497051/091451cdaf1d/ADVS-11-2406936-g007.jpg

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本文引用的文献

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HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice.HDAC9 通过介导 G2/M 期上皮细胞周期阻滞导致雄性小鼠肾脏纤维化。
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Neuraminidase 1 promotes renal fibrosis development in male mice.神经氨酸酶 1 促进雄性小鼠肾脏纤维化的发展。
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