Targeting Src homology phosphatase 2 ameliorates mouse diabetic nephropathy by attenuating ERK/NF-κB pathway-mediated renal inflammation

• Published in: Cell communication and signaling 2023-12, Vol.21 (1), p.362-362, Article 362
• Main Authors: Yu, Che, Li, Zhuo, Nie, Cuili, Chang, Lei, Jiang, Tao
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Biopsy; Creatinine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - drug therapy; Diabetic nephropathy; ERK/NF-κB pathway; Glucose; Homology; Humans; Inflammation; Inflammation - metabolism; Kidneys; Kinases; Medical research; Metabolism; Mice; Molecular modelling; Nephropathy; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Pathology; Phosphatase; Proteins; Renal inflammation; Signal Transduction; Software; Src homology phosphatase 2; Therapeutic targets
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-023-01394-9

Renal inflammation is a pivotal mechanism underlying the pathophysiology of diabetic nephropathy (DN). The Src homology phosphatase 2 (SHP2) has been demonstrated to be linked to diabetes-induced inflammation, yet its roles and explicit molecular mechanisms in DN remain unexplored. Here, we report that SHP2 activity is upregulated in both DN patients and db/db mice. In addition, pharmacological inhibition of SHP2 with its specific inhibitor PHPS1 alleviates DN in db/db mice and attenuates renal inflammation. In vitro, PHPS1 administration prevents inflammatory responses in HK-2 cells stimulated by high glucose (HG). Mechanistically, PHPS1 represses HG-induced activation of the proinflammatory ERK/NF-κB signaling pathway, and these inhibitory effects are blocked in the presence of an ERK specific inhibitor, hence demonstrating that PHPS1 suppresses ERK/NF-κB pathway-mediated inflammation. Moreover, PHPS1 retards ERK/NF-κB pathway activation in db/db mice, and histologically, SHP2 activity is positively correlated with ERK/NF-κB activation in DN patients. Taken together, these findings identify SHP2 as a potential therapeutic target and show that its pharmacological inhibition might be a promising strategy to mitigate DN. Video Abstract.