Table 2. Renal actions of TWEAK/Fn14: key findings from in vitro and in vivo models.
| In vitro key effect | Cell type | Mechanisms | Ref. |
|---|---|---|---|
| Fibrosis | Mesangial cells | TGFbeta1 and fibronectin increase through PKG-I down-regulation | [141] |
| Tubular cells | Endothelial–mesenchymal transition via NF-κB | [142] | |
| Phenotypic changes via NF-κB and ERK activation: F-actin redistribution, loss of epithelial and tight junction proteins, vimentin expression | |||
| Renal fibroblasts | Decrease in collagen I and fibronectin protein levels | [143] | |
| Inflammation | Tubular cells | MCP-1, RANTES increase via NF-κB and JAK2 kinase activation | [144] |
| MCP-1, RANTES, and IL-6 increase | [145] | ||
| CCL21 increase via non-canonical NF-κB activation | [96] | ||
| CXCL16 increase via NF-κB | [146] | ||
| CD74 and DDT increase | [147] | ||
| IL-6 and other chemokines via EGFR activation, ERK activation | [148] | ||
| CXCL10 increase via MAP3K14 and non-canonical NF-κB pathway | [149] | ||
| Modulation of NF-κB components Bcl3 overexpression – which decreases NF-κB transcriptional activity | [150] | ||
| Modulation of NF-κB components: NF-kBiz overexpression – which has anti-inflammatory anti-apoptotic effects | [151] | ||
| Podocytes | MCP-1 increase via NF-κB | [152] | |
| CCL19, RANTES increase via NF-κB | [153] | ||
| CCL21 increase via non-canonical NF-κB pathway | |||
| Induction of multiple inflammatory cytokines/chemokines and adhesion molecules | [110] | ||
| Renal fibroblasts | MCP-1 and RANTES increase via NF-κB | [143] | |
| Mesangial cells | IL-6, IL-8, MCP-1, and CCL5 increase via NF-κB | [85] | |
| Induction of multiple inflammatory cytokines/chemokines and adhesion molecules | [110] | ||
| MCP-1, RANTES, CXCL10, and CXCL1 increase | [109] | ||
| Proliferation | Tubular cells | Cell number increase, cyclin D1 expression via MAPK (ERK/p38), PI3K/Akt, NF-κB | [114] |
| Mesangial cells | Promotion of cell proliferation and cell cycle activity | [85] | |
| Renal fibroblasts | Increase in mitosis number, cyclin D1 expression via Ras/ERK pathway | [143] | |
| Cell death | Tubular cells | (Late) Necroptosis via RIPK1, RIPK3, MLKL | [154] |
| Apoptosis and increased inflammatory gene expression | [155] | ||
| In an inflammatory milieu, induction of apoptosis, activation of caspase-8, -9 -3, Bid cleavage and mitochondrial injury | [115] | ||
| Others | Tubular cells | Klotho down-regulation via NF-κB | [156] |
| MAGED2 up-regulation – modulation of electrolyte transport | [157] | ||
| PGC-1alpha and mitochondrial function down-regulation | [158] | ||
| Endothelial cells | Endothelin-1 increase and ECE1 up-regulation via AP-1 and NF-kB | [159] | |
| Cell growth and migration, enhanced FGF-2 and VEGF-A mitogenic activity | [81] | ||
| Vascular smooth muscle cells | Enhanced inorganic phosphate-induced calcification via both canonical and non-canonical NF-κB pathways | [94] |
| In vivo eperimental model | Intervention | Effect | Ref. |
|---|---|---|---|
| Healthy state | TWEAK administration | Increase in inflammation (chemokines and IL-6) via NF-κB activation | [145] |
| Increase in inflammation (CCL21) via non-canonical NF-κB | [96] | ||
| Increase in inflammation (CXCL16 and CD3 infiltration) via NF-κB | [146] | ||
| Klotho reduction | [156] | ||
| PGC-1alpha reduction | [158] | ||
| Folic acid nephropathy | Anti-TWEAK AB | Reduction in inflammation (chemokines and IL-6) | [145] |
| TWEAK-KO mice | Reduction in apoptosis and proliferation and renal function improvement | [114] | |
| Anti-TWEAK AB TWEAK-KO mice | Reduction in inflammation (CCL21) | [96] | |
| Anti-TWEAK AB | Reduction in inflammation (CXCL16 and CD3 infiltration) | [146] | |
| Anti-TWEAK AB TWEAK-KO mice | Reversal in klotho down-regulation | [156] | |
| Anti-TWEAK AB | Reversal PGC-1alpha | [158] | |
| I/R injury | Fn14 blockade | Reduction in fibrosis and increased survival | [161] |
| HFD-fed ApoE-KO mice | TWEAK administration | Increase in inflammation (RANTES, MCP-1, macrophage infiltration) via NF-κB | [162] |
| Anti-TWEAK AB | Reduction in inflammation (RANTES, MCP-1, macrophage infiltration) | ||
| cGVH-induced lupus | Fn14 blockade | Reduction in IgG deposition, IL-6, MCP-1, RANTES, IP-10, macrophage infiltration Reduction in proteinuria |
[163] |
| Anti-TWEAK AB | Reduction in inflammation Reduction in proteinuria |
||
| Unilateral nephrectomy | TWEAK-KO mice | Reduction in tubular cell proliferation in the remnant kidney | [114] |
| Ureter ligation | TWEAK-KO mice | Reduction in apoptosis, inflammation, and fibrosis | [143] |
| Adeno-TWEAK | Increase in apoptosis, inflammation, and fibrosis | [143] |
Abbreviations: AB: antibody; AP-1: activator protein 1; Bcl3: B-cell lymphoma 3-encoded protein; CCL19: chemokine (C–C motif) ligand 19; CCL21: chemokine (C–C motif) ligand 21; CD74: cluster of differentiation 74; CXCL1: chemokine (C–X–C motif) ligand 1; CXCL10: C–X–C motif chemokine 10 (also known as IP-10); CXCL16: chemokine (C–X–C motif) ligand 16; DDT: d-dopachrome tautomerase cytokine (also known as MIF-2); ECE-1: endothelin-converting enzyme-1; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; FGF-2: fibroblast growth factor 2; IL: interleukin; I/R: ischemia/reperfusion; JAK2: Janus Kinase 2; KO: knockout; MAGED2: melanoma antigen-encoding gene D2; MAPK: mitogen-activated protein kinase; MAP3K14: mitogen-activated protein kinase kinase kinase 14 (also known as NIK); MCP-1: monocyte chemoattractant protein 1; MLKL: mixed lineage domain-like protein; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NF-kBiz: NF-κBInhibitor Zeta; PGC-1 alpha: peroxisome proliferator-activated receptor-γ coactivador-1 alpha; PI3K: phosphoinositide 3-kinase; PKG-I: protein kinase G-I; RANTES: regulated on activation, normal T cell expressed and secreted (also known as CCL5); RIPK: receptor interacting protein kinase; TGFbeta1: transforming growth factor beta 1; VEGF-A: vascular endothelial growth factor A.