Abstract
Members of the TNF superfamily participate in kidney disease. Tumor necrosis factor (TNF) and Fas ligand regulate renal cell survival and inflammation, and therapeutic targeting improves the outcome of experimental renal injury. TNF-related apoptosis-inducing ligand (TRAIL and its potential decoy receptor osteoprotegerin are the two most upregulated death-related genes in human diabetic nephropathy. TRAIL activates NF-kappaB in tubular cells and promotes apoptosis in tubular cells and podocytes, especially in a high-glucose environment. By contrast, osteoprotegerin plays a protective role against TRAIL-induced apoptosis. Another family member, TNF-like weak inducer of apoptosis (TWEAK induces inflammation and tubular cell death or proliferation, depending on the microenvironment. While TNF only activates canonical NF-kappaB signaling, TWEAK promotes both canonical and noncanonical NF-kappaB activation in tubular cells, regulating different inflammatory responses. TWEAK promotes the secretion of MCP-1 and RANTES through NF-kappaB RelA-containing complexes and upregulates CCl21 and CCL19 expression through NF-kappaB inducing kinase (NIK-) dependent RelB/NF-kappaB2 complexes. In vivo TWEAK promotes postnephrectomy compensatory renal cell proliferation in a noninflammatory milieu. However, in the inflammatory milieu of acute kidney injury, TWEAK promotes tubular cell death and inflammation. Therapeutic targeting of TNF superfamily cytokines, including multipronged approaches targeting several cytokines should be further explored.
Highlights
Tumor necrosis factor (TNF) was isolated and cloned 25 years ago [1, 2]
The pathogenic role of TNF as well as the potential benefits of modulating TNF activity has been shown in models of immune complex-mediated glomerulonephritis, lupus nephritis, antineutrophil cytoplasmic antibodies (ANCA-) associated glomerulonephritis, minimal change disease, diabetic nephropathy (DN), acute kidney injury (AKI), obstructive uropathy, and kidney allograft rejection [14, 15, 19, 21, 23,24,25,26]
It is difficult to extrapolate from cell culture studies to the in vivo situation, the low level of apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) in cultured tubular cells is consistent with the slow loss of renal function, over years, characteristic of DN [113]
Summary
Tumor necrosis factor (TNF) was isolated and cloned 25 years ago [1, 2]. This molecule became the prototype of a growing familyof related proteins called the TNF superfamily (TNFSF) that share common features. Most members of the family are synthesized as type II transmembrane proteins and share a common structural motif, the TNF homology domain (THD), that mediates self-trimerization and receptor binding [3, 4]. Ligand activation of TNFRSF members modulates cell proliferation, survival, differentiation, and apoptosis [9]. Such cellular events participate in a broad array of biological processes such as inflammation, fibrosis, the immune response, and tissue repair [10]. TNFSF/TNFRSF members mediate different functions, in different tissues that depend on the surrounding milieu. Unraveling their complex and pleiotropic actions will be essential for their use as therapeutic targets
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
