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Renal cell–expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis
Volker Vielhauer, … , George Stavrakis, Tanya N. Mayadas
Volker Vielhauer, … , George Stavrakis, Tanya N. Mayadas
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1199-1209. https://doi.org/10.1172/JCI23348.
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Article Nephrology

Renal cell–expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis

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Abstract

TNF is essential for the development of glomerulonephritis, an immune-mediated disorder that is a major cause of renal failure worldwide. However, TNF has proinflammatory and immunosuppressive properties that may segregate at the level of the 2 TNF receptors (TNFRs), TNFR1 and TNFR2. TNFR1-deficient mice subjected to immune complex–mediated glomerulonephritis developed less proteinuria and glomerular injury, and fewer renal leukocyte infiltrates at early time points after disease induction, and this was associated with a reduced systemic immune response to nephrotoxic rabbit IgG. However, proteinuria and renal pathology were similar to those in wild-type controls at later time points, when lack of TNFR1 resulted in excessive renal T cell accumulation and an associated reduction in apoptosis of these cells. In sharp contrast, TNFR2-deficient mice were completely protected from glomerulonephritis at all time points, despite an intact systemic immune response. TNFR2 was induced on glomerular endothelial cells of nephritic kidneys, and TNFR2 expression on intrinsic cells, but not leukocytes, was essential for glomerulonephritis and glomerular complement deposition. Thus, TNFR1 promotes systemic immune responses and renal T cell death, while intrinsic cell TNFR2 plays a critical role in complement-dependent tissue injury. Therefore, therapeutic blockade specifically of TNFR2 may be a promising strategy in the treatment of immune-mediated glomerulonephritis.

Authors

Volker Vielhauer, George Stavrakis, Tanya N. Mayadas

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Figure 1

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Wild-type and TNFR1-deficient, but not TNFR2-deficient, mice develop alb...
Wild-type and TNFR1-deficient, but not TNFR2-deficient, mice develop albuminuria with hypoalbuminemia, hypercholesterolemia, and elevated serum creatinine levels at day 21. (A) Albuminuria was evaluated at indicated days after injection of nephrotoxic serum (n = 9 per group). (B) Serum levels for albumin, cholesterol, and creatinine were determined at day 21 (n = 9 per group). The dotted lines indicate baseline values observed in normal wild-type mice. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with wild-type.
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