The Src-Family Kinases Hck, Fgr and Lyn Drive Immune Complex-Mediated Glomerulonephritis Through the Syk Tyrosine Kinase.

While immune complex-mediated glomerulonephritis causes severe kidney dysfunction in diseases like lupus nephritis, the signaling pathways involved are poorly understood. Here we tested the role of the Src-family kinases Hck, Fgr and Lyn, primarily expressed in innate immune cells, in immune complex-mediated glomerulonephritis. Hck, Fgr and Lyn expression increased in human lupus nephritis, as well as in mouse nephrotoxic nephritis triggered by sheep antiserum against mouse glomerular components (nephrotoxic serum). Nephrotoxic serum induced robust albuminuria, serum creatinine level increase, hematuria and ascites in wild-type but not in Hck-/-Fgr-/-Lyn-/- mice. The Hck-/-Fgr-/-Lyn-/- mutation also abrogated crescent formation and leukocyte infiltration. However, the glomerular IgG/complement deposition and the humoral immune response against sheep IgG were not affected. Transplantation of Hck-/-Fgr-/-Lyn-/- bone marrow cells transferred disease protection to wild-type recipients. Mixed bone marrow chimeric experiments revealed an indirect role for Hck, Fgr and Lyn in leukocyte recruitment. Src-family kinases mediated immune complex-induced activation of Syk, a recently proposed therapeutic target. Our results suggest that myeloid Src-family kinases are indispensable for nephrotoxic nephritis. Inhibitors targeting those kinases may provide therapeutic benefit in immune complex-mediated glomerulonephritis.