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Close relations between podocyte injuries and membranous proliferative glomerulonephritis in autoimmune murine models
Junpei Kimura1, Osamu Ichii, Saori Otsuka
1Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Background:
Membranous proliferative glomerulonephritis (MPGN) is a major primary cause of chronic kidney disease (CKD). Podocyte injury is crucial in the pathogenesis of glomerular disease with proteinuria, leading to CKD. To assess podocyte injuries in MPGN, the pathological features of spontaneous murine models were analyzed.
Methods:
The autoimmune-prone mice strains BXSB/MpJ-Yaa and B6.MRL-(D1Mit202-D1Mit403) were used as the MPGN models, and BXSB/MpJ-Yaa(+) and C57BL/6 were used as the respective controls. In addition to clinical parameters and glomerular histopathology, the protein and mRNA levels of podocyte functional markers were evaluated as indices for podocyte injuries. The relation between MPGN pathology and podocyte injuries was analyzed by statistical correlation.
Results:
Both models developed MPGN with albuminuria and elevated serum anti-double-strand DNA (dsDNA) antibody levels. BXSB/MpJ-Yaa and B6.MRL showed severe proliferative lesions with T and B cell infiltrations and membranous lesions with T cell infiltrations, respectively. Foot process effacement and microvillus-like structure formation were observed ultrastructurally in the podocytes of both MPGN models. Furthermore, both MPGN models showed a decrease in immune-positive areas of nephrin, podocin and synaptopodin in the glomerulus, and in the mRNA expression of Nphs1, Nphs2, Synpo, Actn4, Cd2ap, and Podxl in the isolated glomerulus. Significant negative correlations were detected between serum anti-dsDNA antibody levels and glomerular Nphs1 expression, and between urinary albumin-to-creatinine ratio and glomerular expression of Nphs1, Synpo, Actn4, Cd2ap, or Podxl.
Conclusion:
MPGN models clearly developed podocyte injuries characterized by the decreased expression of podocyte functional markers with altered morphology. These data emphasized the importance of regulation of podocyte injuries in MPGN.
Insights
Membranous proliferative glomerulonephritis (MPGN) causes chronic kidney disease (CKD) through podocyte injury. This study analyzed MPGN mouse models, revealing decreased podocyte marker expression and altered morphology, highlighting the need to regulate podocyte injury in MPGN.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Membranous proliferative glomerulonephritis (MPGN) is a primary cause of chronic kidney disease (CKD).
- Podocyte injury is a critical factor in the development of glomerular diseases and proteinuria.
- Understanding podocyte injury in MPGN is essential for managing CKD progression.
Purpose of the Study:
- To investigate podocyte injuries in spontaneous murine models of MPGN.
- To analyze the pathological features and molecular markers associated with podocyte damage in MPGN.
- To establish the relationship between MPGN pathology and the extent of podocyte injury.
Main Methods:
- Utilized autoimmune-prone mouse strains (BXSB/MpJ-Yaa and B6.MRL) as MPGN models, with appropriate controls.
- Assessed clinical parameters, glomerular histopathology, and protein/mRNA levels of podocyte functional markers.
- Employed statistical correlation to analyze the relationship between MPGN pathology and podocyte injury markers.
Main Results:
- MPGN models exhibited albuminuria and elevated anti-double-strand DNA (dsDNA) antibody levels.
- Histopathology revealed proliferative and membranous lesions with immune cell infiltrations.
- Ultrastructural analysis showed podocyte foot process effacement and decreased expression of key podocyte markers (nephrin, podocin, synaptopodin) and their corresponding mRNA.
- Significant negative correlations were found between anti-dsDNA antibody levels/albuminuria and podocyte marker expression.
Conclusions:
- MPGN mouse models demonstrate significant podocyte injury, characterized by morphological changes and reduced expression of functional markers.
- These findings underscore the critical role of podocyte injury in MPGN pathogenesis.
- Targeting and regulating podocyte injury is crucial for managing MPGN and preventing CKD progression.
