Increasing evidence implicates chronic inflammation as the main pathological cause of diabetic nephropathy (DN). Exploration of key targets in the inflammatory pathway may provide new treatment options for DN. Here, we aim to investigate the role of Src Homology 2 Containing Protein Tyrosine Phosphatase 2 (SHP2) in macrophages and its association with DN. The upregulated phosphorylation of SHP2 was detected in macrophages of both diabetic patients and mouse model. Using the macrophage-specific SHP2 knockout mice (SHP2-MKO) and SHP2fl/fl mice injected with streptozotocin (STZ), we showed that SHP2-MKO significantly attenuated renal dysfunction, collagen deposition, fibrosis, and inflammatory response in STZ-induced diabetic mice. RNA-sequencing analysis using primary mouse peritoneal macrophages (MPMs) showed that SHP2 deletion mainly affects mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-ĸB) signaling pathway and MAPKs/NF-ĸB-dependent inflammatory cytokine release in MPMs. Further study indicated that SHP2-deficient macrophages failed to release cytokines that induce phenotype transition and fibrosis in renal cells. Administration with a pharmacological SHP2 inhibitor, SHP099, remarkably protected kidneys in both type 1 and type 2 diabetic mice. In conclusion, these results identify macrophage SHP2 as a new accelerator of DN and suggest that SHP2 inhibition may be a therapeutic option for DN patients.

中文翻译：

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巨噬细胞 SHP2 缺陷通过抑制 MAPK/NF-ĸB 依赖性炎症减轻糖尿病肾病

越来越多的证据表明慢性炎症是糖尿病肾病（DN）的主要病理原因。探索炎症通路中的关键靶点可能为 DN 提供新的治疗选择。在这里，我们的目的是研究含有蛋白酪氨酸磷酸酶 2 (SHP2) 的 Src 同源 2 在巨噬细胞中的作用及其与 DN 的关系。在糖尿病患者和小鼠模型的巨噬细胞中检测到 SHP2 磷酸化上调。使用巨噬细胞特异性 SHP2 敲除小鼠 (SHP2-MKO) 和注射链脲佐菌素 (STZ) 的 SHP2fl/fl 小鼠，我们发现 SHP2-MKO 显着减轻 STZ 诱导的糖尿病小鼠的肾功能障碍、胶原沉积、纤维化和炎症反应。使用原代小鼠腹腔巨噬细胞 (MPM) 进行的 RNA 测序分析表明，SHP2 缺失主要影响丝裂原激活蛋白激酶 (MAPK) 和核因子 kappa B (NF-ĸB) 信号通路以及 MAPKs/NF-ĸB 依赖性炎症细胞因子的释放。 MPM。进一步的研究表明，SHP2缺陷的巨噬细胞无法释放诱导肾细胞表型转变和纤维化的细胞因子。使用药理学 SHP2 抑制剂 SHP099 可以显着保护 1 型和 2 型糖尿病小鼠的肾脏。总之，这些结果将巨噬细胞 SHP2 确定为 DN 的新加速器，并表明 SHP2 抑制可能是 DN 患者的治疗选择。