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Updated: Jun 2, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
IGFBP2 and IGFBP4 interact to activate complement pathway in diabetic kidney disease
Jieling Liang1,2, Yangxiao Huang2, Daping Peng2
1Guangdong Medical University, Dongguan, China.
Background:
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. Overactivation of the complement pathway in DKD remains poorly understood.
Methods:
Blood samples were collected from patients 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 DKD patients. The levels of IGFBP2 and IGFBP4 increased in DKD mice, accompanied by the activation of the complement pathway, and a deterioration in renal function. High glucose and serum from DKD mice stimulated an increase in the levels of IGFBP2 and IGFBP4 in HK-2 cells. The supernatant from HK-2 cells was used to culture THP-1 cells, resulted in an increase in the M1 type of THP-1 cells, a decrease in the M2 type, and activation of the complement pathway. The supernatant from THP-1 cells affected the growth of primary human renal podocytes. The exogenous addition of IGFBP2 and IGFBP4 proteins to primary human renal podocytes did not affect their growth. However, when human renal podocytes were cultured with the supernatant from THP-1 cells, the growth of the podocytes was affected.
Conclusions:
IGFBP2 and IGFBP4 interact to stimulate the activation of the complement pathway in macrophages, which induces podocyte apoptosis and subsequently promotes the development of DKD.
Insights
Insulin-like growth factor-binding proteins 2 (IGFBP2) and 4 (IGFBP4) activate the complement pathway in macrophages, leading to podocyte apoptosis and diabetic kidney disease (DKD) progression.
Area of Science:
- Nephrology
- Immunology
- Endocrinology
Background:
- Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide.
- Insulin-like growth factor-binding proteins 2 (IGFBP2) and 4 (IGFBP4) are emerging as potential DKD biomarkers.
- The role of complement pathway overactivation in DKD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the roles of IGFBP2, IGFBP4, and complement activation in DKD.
- To elucidate the molecular mechanisms linking these factors to DKD development.
Main Methods:
- Proteomic analysis of blood samples from DKD patients.
- In vitro studies using HK-2 and THP-1 cell lines.
- In vivo experiments in DKD mouse models.
- Investigation of primary human renal podocyte responses.
Main Results:
- Elevated IGFBP2 and IGFBP4 levels were found in DKD patients and mice.
- DKD mice showed increased IGFBP2/IGFBP4, complement activation, and worsened renal function.
- High glucose and DKD serum increased IGFBP2/IGFBP4 in HK-2 cells, promoting M1 macrophage polarization and complement activation.
- Macrophage-derived factors, not IGFBP2/IGFBP4 alone, impaired podocyte growth.
Conclusions:
- IGFBP2 and IGFBP4 interact to activate the complement pathway in macrophages.
- This macrophage-mediated complement activation induces podocyte apoptosis.
- The IGFBP2/IGFBP4-macrophage-complement axis is a key driver in diabetic kidney disease progression.
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