Abstract
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.
Highlights
IgA nephropathy (IgAN) is the most frequently occurring form of primary glomerulonephritis worldwide, affecting 20%–50% of patients [1]
To further implicate the contribution of Gr1−/CD115+ monocytes to the pathogenesis of IgAN, we evaluated the correlation between the number of Gr1−/CD115+ monocytes and the inflammatory process
We demonstrate here that the A proliferation-inducing ligand (APRIL) signaling pathway is involved in the pathogenesis of IgAN
Summary
IgA nephropathy (IgAN) is the most frequently occurring form of primary glomerulonephritis worldwide, affecting 20%–50% of patients [1]. It has been reported that 30%–40% of patients with IgAN progress to end-stage renal disease within 20 years. IgAN is considered to be a major cause of end-stage renal disease in many countries [4,5]. It is widely accepted that IgA1 molecules lacking galactosyl residues in the hinge region of the heavy chain are recognized by glycan-specific antibodies and that subsequent binding forms nephritogenic IgA1–IgG immune complexes [1,6]. When these aberrantly glycosylated IgA1 and IgA1–IgG immune complexes are deposited in the glomerulus, they induce eventual renal injury. There are no effective treatment strategies to control the activities of nephritogenic effector molecules
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