Idiopathic membranous nephropathy (MN) is an autoimmune-mediated
glomerulonephritis and the most common cause of idiopathic
nephrotic syndrome in adult humans. A
tumor necrosis factor α (TNF-α)-mediated inflammatory response via
TNF receptor 1 (
TNFR1) and
TNFR2 has been proposed as a pathogenic factor. In this study, we assessed the therapeutic response to blocking TNF signaling in experimental MN. Murine MN was induced experimentally by cationic
bovine serum albumin (cBSA);
phosphate-buffered saline was used in control mice. In MN mice, TNF was inhibited by
etanercept blocking of
TNFR1/
TNFR2 or the preligand assembly domain fusion
protein (PLAD.Fc), a small fusion
protein that can preferentially block
TNFR1 signaling. Disease severity and possible mechanisms were assessed by analyzing the metabolic and histopathology profiles, lymphocyte subsets,
immunoglobulin production, oxidative stress, and apoptosis. cBSA-induced MN mice exhibited typical
nephrotic syndrome and renal histopathology. MN mice given
etanercept or PLAD.Fc did not exhibit significant reduction of
proteinuria, amelioration of glomerular lesions, or attenuation of
immune complex deposition. Immune cell subsets, serum
immunoglobulin levels, production of
reactive oxygen species, and cell apoptosis in the kidney were not altered by TNF inhibition. By contrast, MN mice receiving
etanercept or PLAD.Fc exhibited significantly decreased infiltration of immune cells into the kidney. These results show that the
therapeutic effects of blocking
TNFR1 and/or
TNFR2 signaling in experimental MN are not clinically effective. However, TNF signaling inhibition significantly attenuated renal immune cell infiltration in experimental MN.