Pathogenic Role of a Proliferation-Inducing Ligand (APRIL) in Murine IgA Nephropathy.
A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily. Despite advances in clinical and genetic studies, the details of the pathological roles of APRIL in IgA nephropathy (IgAN) remain to be fully defined. The present study aimed to further assess the pathological role of APRIL using a mouse model of IgAN. Mice with IgAN designated "grouped ddY" (gddY) were intraperitoneally administered an anti-APRIL monoclonal antibody (anti-APRIL Ab) or control IgG (Control Ab) twice each week for 2 weeks starting during the early stage of IgAN (6-7 weeks of age). Urinary albumin, serum IgA, and glomerular IgA deposition were evaluated. We further assessed the inflammatory responses during treatment by measuring the levels of the chemokine fractalkine (FKN) and its receptor CX3CR1 as well as the level of peripheral blood monocytosis. Anti-APRIL Ab treatment significantly decreased albuminuria and tissue damage combined with decreases in serum IgA levels and deposition of glomerular IgA. In contrast, the abundance of IgA+/B220+ or CD138+/B220+ B cells in the spleen and bone marrow, respectively, was unchanged. Treating gddY mice with anti-April Ab reduced the overexpression of FKN/CX3CR1 in the kidney and the increase in the population of circulating Gr1-/CD115+ monocytes. The size of the population of Gr1-/CD115+ monocytes correlated with renal FKN and urinary albumin levels. Moreover, mice treated with anti-APRIL Ab exhibited reduced progression of IgAN, serum IgA levels, and glomerular IgA deposition as well as an attenuated inflammatory process mediated by FKN-associated activation of monocytes. To the best of our knowledge, this is the first study to implicate the APRIL signal transduction pathway in the pathogenesis of nephrogenic IgA production. Moreover, our findings identify APRIL as a potential target of therapy.
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan; Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea.
Yang Gyun
YG
Kim
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Montserrat
M
Alvarez
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Hitoshi
H
Suzuki
Department of Pathology, Juntendo University, School of Medicine, Tokyo, Japan.
Sachiko
S
Hirose
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Shozo
S
Izui
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Yasuhiko
Y
Tomino
Institut Albert Bonniot, INSERMU823 and Grenoble-Alpes University, La Tronche, France.
Bertrand
B
Huard
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Yusuke
Y
Suzuki
D000419:Albuminuria / Q000097:blood / Q000652:urine; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D005922:Glomerulonephritis, IGA / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000097:blood; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D007070:Immunoglobulin A; D019707:Receptors, Chemokine; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13