Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy
| Autor: | Yusuke Suzuki, Rina Kato, Emiri Hiramoto, Satoko Arai, Kimi Araki, Hitoshi Suzuki, Yuko Makita, Junichiro Nakata, Toru Miyazaki, Akiko Takahata, Kento Kitada |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Kidney Glomerulus
Inflammation urologic and male genital diseases Immune complex formation law.invention Nephropathy Mice Downregulation and upregulation law medicine Animals Humans Complement Activation Receptors Scavenger Mice Inbred BALB C Proteinuria business.industry Glomerulonephritis IGA General Medicine medicine.disease Phenotype Immunoglobulin A Basic Research Nephrology Immunology Recombinant DNA medicine.symptom Apoptosis Regulatory Proteins business Infiltration (medical) |
| Zdroj: | J Am Soc Nephrol |
| ISSN: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2019100987 |
| Popis: | Background IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition. Methods We established an AIM-deficient IgAN model (AIM -/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA -/- gddY) was also generated to further determine the role of AIM. Results In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM -/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA -/- gddY mice. Conclusions AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation. |
| Databáze: | OpenAIRE |
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