IGFBP2 and IGFBP4 Interact to Activate Complement Pathway in Diabetic Nephropathy

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease globally. Recent research has identified insulin-like growth factor-binding proteins 2 (IGFBP2) and 4 (IGFBP4) as potential biomarkers for DKD, suggesting their utility in diagnosis. While overactivation of the complement system is linked to various immune-mediated kidney disorders, the specific mechanisms involved in DKD remain poorly understood. Methods: Blood samples were collected for proteomic analysis, complemented by both in vitro and in vivo experiments to investigate the roles of IGFBP2, IGFBP4, and the complement pathway in DKD. Results: Elevated levels of IGFBP2 and IGFBP4 were observed in the blood of DKD patients. Furthermore, a mouse model of DKD demonstrated increased levels of these proteins, alongside activation of the complement pathway, reduced glucose metabolism, impaired kidney function, and pathological damage to the kidneys. Serum stimulation of HK-2 cells resulted in elevated levels of IGFBP2 and IGFBP4; the supernatant from stimulated HK-2 cells promoted an increase in M1 macrophage polarization while decreasing M2 polarization in THP-1 cells, which was associated with complement pathway activation. Additionally, the supernatant from THP-1 cells increased the apoptosis rate of human renal podocytes. Notably, the exogenous addition of IGFBP2 and IGFBP4 proteins to human renal podocytes did not affect their growth, but the extraction of IGFBP2 and IGFBP4 from THP-1 cell supernatants led to loss of normal podocyte morphology and increased apoptosis rates. This study aims to provide new insights and strategies for the treatment of DKD.Conclusion: IGFBP2 and IGFBP4 interact to activate the complement pathway, enhance M1 macrophage polarization, induce podocyte apoptosis, and consequently contribute to the progression of DKD.