The Signaling Pathway of TNF Receptors: Linking Animal Models of Renal Disease to Human CKD

Abstract

Chronic kidney disease (CKD) has been recognized as a global public health problem. Despite the current advances in medicine, CKD-associated morbidity and mortality remain unacceptably high. Several studies have highlighted the contribution of inflammation and inflammatory mediators to the development and/or progression of CKD, such as tumor necrosis factor (TNF)-related biomarkers. The inflammation pathway driven by TNF-α, through TNF receptors 1 (TNFR1) and 2 (TNFR2), involves important mediators in the pathogenesis of CKD. Circulating levels of TNFRs were associated with changes in other biomarkers of kidney function and injury, and were described as predictors of disease progression, cardiovascular morbidity, and mortality in several cohorts of patients. Experimental studies describe the possible downstream signaling pathways induced upon TNFR activation and the resulting biological responses. This review will focus on the available data on TNFR1 and TNFR2, and illustrates their contributions to the pathophysiology of kidney diseases, their cellular and molecular roles, as well as their potential as CKD biomarkers. The emerging evidence shows that TNF receptors could act as biomarkers of renal damage and as mediators of the disease. Furthermore, it has been suggested that these biomarkers could significantly improve the discrimination of clinical CKD prognostic models.

Keywords: CKD; TNF-alpha; TNFR; biomarkers; inflammation.

Figure 1

TNFR1 (a) and TNFR2 (b) mediated signaling pathways. Akt, protein kinase B; AP-1, activator protein-1; ASK-1, apoptosis signal-regulating kinase-1; c-FLIPʟ, cellular FLICE-inhibitory protein; cIAP1/2, cellular inhibitor of apoptosis protein 1 or 2; Etk, endothelial/epithelial protein tyrosine kinase; FADD, Fas-associated death domain; IKK, inhibitor of kappa B kinase; IκB, NF-ĸB inhibitor; JNK, c-jun kinase; LUBAC, linear ubiquitin chain assembly complex; MAPK, mitogen activated protein kinase; MLKL, mixed lineage kinase domain-like protein; NEMO, NF-κB essential modulator; NF-ĸB, nuclear factor kappa B; NIK, NF-κB inducing kinase; PI3K, phosphatidylinositol 3-kinase; RIPK1/3, receptor interacting serine/threonine-protein kinase 1 or 3; SODD, silencer of death domains; TAB, TAK-binding proteins; TAK1, transforming growth factor-beta-activated kinase 1; TNFR1, tumor necrosis factor receptor 1; TNFR2, tumor necrosis factor receptor 2; TNF-α, tumor necrosis factor alpha; TRADD, TNF receptor-associated death domain; TRAF1/2, TNF receptor-associated factor 1 or 2.