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

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.

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…Interestingly, the expression of TNFRII (but not TNFRI) on intrinsic renal cells has recently been shown to be important in experimental immune nephritis (38). Additionally, levels of serum TNFRI have been noted to be increased in human systemic lupus erythematosus (17,18).…”

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

“…13,14 Using a monoclonal antibody that specifically detects phosphorylation of serine 283 in SSeCKS, a target residue for aPKC, 12 we detected rapid phosphorylation of SSeCKS in PECs following activation of PKC by the phorbol ester, phorbol 12,13-diacetate, or by soluble TNF-a, the latter a known PKC activator 26 and inflammatory mitogen in the proliferative podocytopathies (Figure 3a). 27,28 This phosphorylation was abrogated by the pan-PKC inhibitor, staurosporine aglycone. The immediate-early upregulation of SSeCKS expression that occurs with mitogenic signaling is also evident in PECs.…”

“…[3][4][5] We hypothesized earlier that patterns of aberrant repair in the proliferative podocytopathies lie on a spectrum of inflammatory injury, [32][33][34] recently identifying the TNF-a-TNFR2 axis as one possible causative pathway. 27,28 Intriguingly, TNF-a is one of a host of mitogenic activators of PKC, 26 inducing PKC phosphorylation of SSeCKS in PECs. This phosphorylation disrupts SSeCKS ability to bind and sequester cyclin D1 [12][13][14] in regulating the proliferative response of PECs, a state mimicked by the lack of SSeCKS in SSeCKS À/À mice.…”

Necroinflammation in Kidney Disease

“…94 Glomerular cell necrosis induces DAMP release that further drives cytokine and chemokine release, leukocyte recruitment, and inflammation. 92 Infiltrating immune cells, in turn, further contribute to necroinflammation by NETosis (neutrophils), 92 cytokine-induced cell death (all proinflammatory leukocytes), 95 or direct T cell-related cytotoxicity. 96 Vascular wall rupture not only facilitates hematuria but also plasma leakage as a major driver of parietal epithelial cell hyperplasia and crescent formation.…”