Table 2 Renal actions of TWEAK/Fn14: key findings from in vitro and in vivo models
In vitro key effectCell typeMechanismsRef.
FibrosisMesangial cellsTGFbeta1 and fibronectin increase through PKG-I down-regulation[141]
Tubular cellsEndothelial–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 fibroblastsDecrease in collagen I and fibronectin protein levels[143]
InflammationTubular cellsMCP-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]
PodocytesMCP-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 fibroblastsMCP-1 and RANTES increase via NF-κB[143]
Mesangial cellsIL-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]
ProliferationTubular cellsCell number increase, cyclin D1 expression via MAPK (ERK/p38), PI3K/Akt, NF-κB[114]
Mesangial cellsPromotion of cell proliferation and cell cycle activity[85]
Renal fibroblastsIncrease in mitosis number, cyclin D1 expression via Ras/ERK pathway[143]
Cell deathTubular 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]
OthersTubular cellsKlotho down-regulation via NF-κB[156]
MAGED2 up-regulation – modulation of electrolyte transport[157]
PGC-1alpha and mitochondrial function down-regulation[158]
Endothelial cellsEndothelin-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 cellsEnhanced inorganic phosphate-induced calcification via both canonical and non-canonical NF-κB pathways[94]
In vivo eperimental modelInterventionEffectRef.
Healthy stateTWEAK administrationIncrease 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 nephropathyAnti-TWEAK ABReduction in inflammation (chemokines and IL-6)[145]
TWEAK-KO miceReduction in apoptosis and proliferation and renal function improvement[114]
Anti-TWEAK AB TWEAK-KO miceReduction in inflammation (CCL21)[96]
Anti-TWEAK ABReduction in inflammation (CXCL16 and CD3 infiltration)[146]
Anti-TWEAK AB TWEAK-KO miceReversal in klotho down-regulation[156]
Anti-TWEAK ABReversal PGC-1alpha[158]
I/R injuryFn14 blockadeReduction in fibrosis and increased survival[161]
HFD-fed ApoE-KO miceTWEAK administrationIncrease in inflammation (RANTES, MCP-1, macrophage infiltration) via NF-κB[162]
Anti-TWEAK ABReduction in inflammation (RANTES, MCP-1, macrophage infiltration)
cGVH-induced lupusFn14 blockadeReduction in IgG deposition, IL-6, MCP-1, RANTES, IP-10, macrophage infiltration
Reduction in proteinuria
[163]
Anti-TWEAK ABReduction in inflammation
Reduction in proteinuria
Unilateral nephrectomyTWEAK-KO miceReduction in tubular cell proliferation in the remnant kidney[114]
Ureter ligationTWEAK-KO miceReduction in apoptosis, inflammation, and fibrosis[143]
Adeno-TWEAKIncrease 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.