TNF receptors: signaling pathways and contribution to renal dysfunction

Abstract

Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders.

Circulating TNF Receptors 1 and 2 Predict Mortality in Patients with End-stage Renal Disease Undergoing Dialysis

“…TNFα is a central proinflammatory cytokine and, at the same time, has immune-regulatory functions. Binding of TNFα to TNFR1 or TNFR2 produces distinct signalling pathways that may promote tissue injury or induce protective responses78. To date, many investigators including us have demonstrated that the TNF pathway is involved in the pathogenesis of various types of renal diseases9272829, and that TNF-related biomarkers are also associated with the levels of albuminuria or GFR1819.…”

“…TNF receptors (TNFRs: TNFR1, TNFR2) belong to the TNF receptor superfamily, a group of type I single transmembrane glycoproteins. Binding of TNFα to TNFR1 or TNFR2 activates signalling pathways that control inflammatory and immune responses, and apoptosis78. We previously demonstrated that the TNF-TNFR2 pathway is involved in the development and/or progression of diabetic nephropathy in the type 2 diabetic model of KK-A y mice, and TNF inhibition with a soluble TNFR2 fusion protein (etanercept) improves albuminuria and renal tissue injury through its anti-inflammatory effect9.…”

The next generation of therapeutics for chronic kidney disease

“…In addition TNFR1 and TNFR2 can be associated with different functions. A Renal protective role for TNFR1 is postulated, since deletion of this receptor is associated with higher systolic pressure and urinary albumin excretion, as well as an altered GFR 9293 . TNFR2 has been shown to exert positive inotropic effects in cardiac myocytes via enhanced calcium handling 94 .…”

“…TNF neutralizing antibodies or TNF receptor knockouts have reduced severity in preclinical rodent models of kidney disease 92,95 . Nevertheless, despite anti-TNF agents having been utilized clinically for more than two decades, there have been few studies examining their clinical activity in kidney disease.…”

“…Nevertheless, despite anti-TNF agents having been utilized clinically for more than two decades, there have been few studies examining their clinical activity in kidney disease. Any studies have been relatively small and have mainly focused on lupus nephritis and FSGS, leaving their potential activity in other forms of CKD progression unaddressed 89,92 .…”