Abstract
TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.
Highlights
Cytokines produced by intrinsic renal cells and infiltrating leukocytes are central mediators of inflammatory kidney diseases
Compartment-specific quantitative PCR revealed a constitutive expression of TNFR1 and TNFR2 in normal mouse glomeruli, with substantially lower transcript levels in tubulointerstitial tissue (Figure 1A)
TNFR1 and TNFR2 were not shed from the surface of mesangial cells upon stimulation, and surface expression of TNFR2 increased after combined stimulation with Tumor necrosis factor-a (TNF) and IFN-c (Figure 2G, 2H), suggesting a robust mesangial TNF receptors (TNFR) signaling capacity in inflammatory conditions
Summary
Cytokines produced by intrinsic renal cells and infiltrating leukocytes are central mediators of inflammatory kidney diseases. The functional role of TNF in GN has been demonstrated in animal models. Systemic administration of TNF induced glomerular damage in rabbits [12] and exacerbated glomerular injury in rats with nephrotoxic serum nephritis (NTN), a model of immune complex-mediated GN [13]. TNF-deficient mice subjected to NTN demonstrated reduced proteinuria, glomerular crescent formation, infiltration of leukocytes, and expression of vascular adhesion molecules [14]. In bone marrow chimeric mice it was shown that intrinsic renal cells are the major source of TNF contributing to renal injury in the NTN model [15,16]. TNF blockade attenuated glomerular lesions and crescent formation in rats developing anti-glomerular basement membrane antibody-induced crescentic GN [17,18,19]
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