Ren Yan, Yu Mengjie, Zheng Danna, He Wenfang, Jin Juan
Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
Department of Nephrology, The First People's Hospital of Hangzhou Lin'an District, Affiliated Lin'an People's Hospital, Hangzhou Medical College, Hangzhou, China.
Arch Med Sci. 2023 Jul 31;20(1):233-247. doi: 10.5114/aoms/170160. eCollection 2024.
Diabetic nephropathy (DN) is a leading cause of kidney failure. Lysozyme (LYZ) is an essential component of innate immunity and exhibits antibacterial properties. However, LYZ has been reported to induce nephropathy, implying a possible association between impaired renal function and lysozyme expression.
Bioinformatics analysis was used to predict the hub gene associated with DN, and the differential expression of the hub gene was confirmed using a mouse model. A mouse model of streptozotocin (STZ)-induced diabetic nephropathy was established to investigate the correlation between DN and LYZ expression, and the functionality of LYZ was verified through knockdown and overexpression experiments conducted . Immunohistochemistry (IHC) was utilized to assess fibrosis-related markers and cytokines, while Masson staining was performed to assess renal fibrosis. Fibroblast proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay. The role of the JAK pathway was confirmed using the JAK inhibitor AG490, and Western blot was used to investigate the underlying mechanisms.
Mechanistically, 25 mM glucose promotes the expression of LYZ in fibroblastic cells, and LYZ may in turn promote the proliferation of renal interstitial fibroblasts. Western blot shows that glucose can activate STAT3 in an LYZ-dependent manner, and the JAK inhibitor AG490 can partially suppress LYZ-induced STAT3 activation. Furthermore, observations have revealed that overexpression of LYZ is associated with the senescent phenotype of renal tubular epithelial cells (RTECs).
Lysozyme promotes kidney fibrosis via the JAK/STAT3 signaling pathway in diabetic nephropathy, and glucose may promote fibroblast proliferation by promoting LYZ auto-secretion.
糖尿病肾病（DN）是肾衰竭的主要原因。溶菌酶（LYZ）是先天免疫的重要组成部分，具有抗菌特性。然而，有报道称LYZ可诱发肾病，这意味着肾功能受损与溶菌酶表达之间可能存在关联。
采用生物信息学分析预测与DN相关的枢纽基因，并使用小鼠模型确认枢纽基因的差异表达。建立链脲佐菌素（STZ）诱导的糖尿病肾病小鼠模型，以研究DN与LYZ表达之间的相关性，并通过进行敲低和过表达实验验证LYZ的功能。利用免疫组织化学（IHC）评估纤维化相关标志物和细胞因子，同时进行Masson染色评估肾纤维化。使用细胞计数试剂盒-8（CCK-8）检测法评估成纤维细胞增殖。使用JAK抑制剂AG490确认JAK通路的作用，并通过蛋白质印迹法研究潜在机制。
从机制上讲，25 mM葡萄糖可促进成纤维细胞中LYZ的表达，而LYZ反过来可能促进肾间质成纤维细胞的增殖。蛋白质印迹显示，葡萄糖可通过LYZ依赖性方式激活STAT3，JAK抑制剂AG490可部分抑制LYZ诱导的STAT3激活。此外，观察结果表明，LYZ的过表达与肾小管上皮细胞（RTEC）的衰老表型有关。
在糖尿病肾病中，溶菌酶通过JAK/STAT3信号通路促进肾脏纤维化，葡萄糖可能通过促进LYZ的自分泌来促进成纤维细胞增殖。
