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Exploring the protective role of DDIT4/mTOR in podocyte integrity through macrophage polarization in diabetic kidney
Jingxuan Shi1,2, Xiansen Wei1, Guming Zou1
1Department of Nephrology, China-Japan Friendship Hospital, Beijing, China.
Objectives:
In this study, we explored the mechanism by which DDIT4 influences the polarization phenotypic transformation of macrophages and inflammation through the regulation of mTOR signaling pathway, providing a new mechanism and target for the treatment of diabetic nephropathy.
Methods:
The degree of inflammation and injury in renal tissues of diabetic kidney disease (DKD) animal model was evaluated using biochemical assays, renal pathology examinations, and Western blot tests. Podocytes and macrophages were isolated from renal tissues to observe the extent of podocyte injury and the quantity and polarization phenotype of macrophage infiltration. Subsequently, the activated M1 macrophage model was constructed and transfected with DDIT4 to evaluate the effect of DDIT4 on the polarization phenotype transformation of macrophages and the expression of inflammatory factors. Finally, the co-culture system of macrophages and podocytes was constructed to detect the cell apoptosis, and the morphology and subcellular structure of podocin were observed by transmission electron microscopy.
Results:
In the DKD animal model, the expression levels of inflammatory factors in renal tissues were significantly higher than those in the control group. Additionally, there was significant damage to the renal podocytes. At the same time, there was a higher number of macrophage infiltrations, predominantly of the M1 polarized phenotype. In the constructed M1 polarized macrophage model, overexpression of DDIT4 can induce the decrease of M1 macrophages and reduce the expression level of inflammatory factors. In the co-culture system of macrophages and podocytes, overexpressed DDIT4 significantly reduced the proportion of podocyte apoptosis and protect the changes of morphology and subcellular structure.
Conclusions:
The ability of DDIT4 to mediate the transformation of macrophage phenotype and reduce inflammation reveals its potential as an innovative drug discovery target for DKD. Further exploration and validation of the therapeutic potential of DDIT4 may provide effective interventions to address unaddressed clinical needs in the treatment of DKD.
Insights
DDIT4 regulates macrophage polarization and inflammation via the mTOR pathway, offering a new therapeutic target for diabetic nephropathy. This study shows DDIT4 reduces M1 macrophages and podocyte apoptosis in diabetic kidney disease models.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Diabetic kidney disease (DKD) is characterized by inflammation and renal podocyte injury.
- Macrophage polarization plays a critical role in DKD pathogenesis.
- The mTOR signaling pathway is implicated in macrophage function and inflammation.
Purpose of the Study:
- To investigate the role of DDIT4 in macrophage polarization and inflammation in DKD.
- To explore DDIT4 as a potential therapeutic target for DKD treatment.
Main Methods:
- DKD animal model establishment and evaluation using biochemical assays, pathology, and Western blot.
- Isolation and analysis of podocytes and macrophages from renal tissues.
- Construction of M1 macrophage and macrophage-podocyte co-culture models to assess DDIT4's effects.
- Transmission electron microscopy for ultrastructural analysis.
Main Results:
- DKD model exhibited elevated renal inflammation, podocyte damage, and M1 macrophage infiltration.
- Overexpression of DDIT4 in M1 macrophages reduced M1 phenotype and inflammatory factor expression.
- DDIT4 overexpression in co-culture systems decreased podocyte apoptosis and protected podocyte morphology.
Conclusions:
- DDIT4 effectively mediates macrophage phenotype transformation and reduces inflammation in DKD.
- DDIT4 presents a promising therapeutic target for DKD intervention.
- Further research on DDIT4 could lead to novel treatments for unmet clinical needs in DKD.
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