Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy

Akiko Takahata; Satoko Arai; Emiri Hiramoto; Kento Kitada; Rina Kato; Yuko Makita; Hitoshi Suzuki; Junichiro Nakata; Kimi Araki; Toru Miyazaki; Yusuke Suzuki

doi:10.1681/ASN.2019100987

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Significance Statement

Apoptosis inhibitor of macrophage (AIM) protein is involved in various diseases. It removes dead cells in urinary tubules, which aids recovery in AKI. Moreover, dysfunctional AIM scavenging in macrophages is a well known cause of feline renal failure. This study clarified the role of AIM in IgA nephropathy (IgAN) in a mouse model. AIM-deficient IgAN mice (AIM^−/−gddY mice) showed IgA deposition similar to that of wild-type gddY mice but did not have glomerular accumulation of IgM/IgG/complement and subsequent regional inflammation, avoiding glomerular sclerosis, proteinuria, and hematuria. IgM/IgG-IgA immune complex formed by recombinant AIM restored the IgAN phenotype. Elucidating the role of AIM in IgAN may facilitate development of new IgAN therapies.

Abstract

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.

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