Abstract
The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-κB) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-κB pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-κB pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-κB activation in kidney disease and on its contribution to TWEAK actions in vivo.
Highlights
The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing
Recent evidence suggests a role for TNF superfamily member Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, Apo3L, or TNFSF12) in both AKI and CKD, where it has been shown to regulate cell death, inflammation, and fibrosis through activation of the TWEAK receptor Fn14 and a variety of intracellular signaling pathways, including the transcription factor nuclear factor-kappa B (NF-κB) [4, 5] (Figure 1)
We review current information on TWEAK, non-canonical NF-κB activation, and kidney disease
Summary
The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. TWEAK activation of the non-canonical NF-κB pathways promotes inflammatory responses in tubular cells. Recent evidence suggests a role for TNF superfamily member Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, Apo3L, or TNFSF12) in both AKI and CKD, where it has been shown to regulate cell death, inflammation, and fibrosis through activation of the TWEAK receptor Fn14 and a variety of intracellular signaling pathways, including the transcription factor nuclear factor-kappa B (NF-κB) [4, 5] (Figure 1).
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