American Diabetes Association
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Macrophage SHP2 Deficiency Alleviates Diabetic Nephropathy via Suppression of MAPK/NF-κB-Dependent Inflammation

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posted on 2024-02-23, 20:46 authored by Xue Han, Jiajia Wei, Ruyi Zheng, Yu Tu, Mengyang Wang, Lingfeng Chen, Zheng Xu, Lei Zheng, Chao Zheng, Qiaojuan Shi, Huazhong Ying, Guang Liang
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-κB) signaling pathway and MAPKs/NF-κB-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.


This study was supported by the Zhejiang Provincial Key Scientific Project (Grant No. 2021C03041 to G.L.), the Zhejiang Provincial Medicine and Health Science and Technology Project (Grant No. 2024KY932 to X.H.), the Natural Science Foundation of Zhejiang Province (Grant No. LTGD24C040007 to Q.S.).