TWEAK, a multifunctional cytokine in kidney injury
2011; Elsevier BV; Volume: 80; Issue: 7 Linguagem: Inglês
10.1038/ki.2011.180
ISSN1523-1755
AutoresAna B. Sanz, María Dolores Sánchez-Niño, Alberto Ortíz,
Tópico(s)interferon and immune responses
ResumoTumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily that activates the Fn14 receptor. TWEAK may regulate cell proliferation, cell death, cell differentiation, and inflammation. TWEAK and Fn14 are constitutively present in the kidney. Sources of TWEAK and Fn14 include intrinsic renal cells and infiltrating leukocytes. Basal Fn14 expression is low, but Fn14 is greatly upregulated during kidney injury. TWEAK contributes to kidney inflammation promoting chemokine secretion by renal cells through canonical and non-canonical NFκB activation. TWEAK also promotes tubular cell proliferation. However, TWEAK induces mesangial and tubular cell apoptosis under proinflammatory conditions. These data indicate that TWEAK is a multifunctional cytokine in the kidney, the actions of which are modulated by the cell microenvironment. Confirmation of the role of TWEAK in kidney injury came from functional studies in experimental animal models. The TWEAK/Fn14 pathway contributed to cell death and interstitial inflammation during acute kidney injury, to glomerular injury in lupus nephritis, to hyperlipidemia-associated kidney injury, and to tubular cell hyperplasia following unilateral nephrectomy. Circulating soluble TWEAK (sTWEAK) levels are a potential biomarker of adverse outcomes in chronic kidney disease and urinary sTWEAK is a potential biomarker of lupus nephritis activity. The available evidence suggests that TWEAK may provide diagnostic information and be a therapeutic target in renal injury. Its role in human kidney disease should be further explored. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily that activates the Fn14 receptor. TWEAK may regulate cell proliferation, cell death, cell differentiation, and inflammation. TWEAK and Fn14 are constitutively present in the kidney. Sources of TWEAK and Fn14 include intrinsic renal cells and infiltrating leukocytes. Basal Fn14 expression is low, but Fn14 is greatly upregulated during kidney injury. TWEAK contributes to kidney inflammation promoting chemokine secretion by renal cells through canonical and non-canonical NFκB activation. TWEAK also promotes tubular cell proliferation. However, TWEAK induces mesangial and tubular cell apoptosis under proinflammatory conditions. These data indicate that TWEAK is a multifunctional cytokine in the kidney, the actions of which are modulated by the cell microenvironment. Confirmation of the role of TWEAK in kidney injury came from functional studies in experimental animal models. The TWEAK/Fn14 pathway contributed to cell death and interstitial inflammation during acute kidney injury, to glomerular injury in lupus nephritis, to hyperlipidemia-associated kidney injury, and to tubular cell hyperplasia following unilateral nephrectomy. Circulating soluble TWEAK (sTWEAK) levels are a potential biomarker of adverse outcomes in chronic kidney disease and urinary sTWEAK is a potential biomarker of lupus nephritis activity. The available evidence suggests that TWEAK may provide diagnostic information and be a therapeutic target in renal injury. Its role in human kidney disease should be further explored. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, Apo3L, TNFSF12) is a member of the TNF superfamily (TNFSF).1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar Members of the TNFSF are widely expressed and have important roles in immune responses, inflammation, cell homeostasis, and tissue repair.2.Foster D. Parrish-Novak J. 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Each ligand binds to one or more members of the TNF receptor superfamily (TNFRSF).4.Locksley R.M. Killeen N. Lenardo M.J. The TNF and TNF receptor superfamilies: integrating mammalian biology.Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2053) Google Scholar, 5.Bodmer J.L. Schneider P. Tschopp J. The molecular architecture of the TNF superfamily.Trends Biochem Sci. 2002; 27: 19-26Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar TNFRSF receptors have an extracellular domain with a ligand-binding region and a cytoplasmic tail with one or more adaptor protein-binding sites, which activate signal cascades. The human TWEAK gene encodes a type II transmembrane glycoprotein of 249 amino acids (aa). The C-terminal extracellular domain (206-aa) contains the receptor-binding site and a potential N-glycosylation site.1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar This domain is proteolytically processed, probably, at one or both of two furin consensus cleavage sites.1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar, 6.Brown S.A. Ghosh A. Winkles J.A. Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway.J Biol Chem. 2010; 285: 17432-17441Crossref PubMed Scopus (35) Google Scholar The result from this proteolysis is a 156-aa-soluble TWEAK isoform (sTWEAK).1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar, 7.Nakayama M. Kayagaki N. Yamaguchi N. et al.Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity.J Exp Med. 2000; 192: 1373-1380Crossref PubMed Scopus (123) Google Scholar, 8.Winkles J.A. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting.Nat Rev Drug Discov. 2008; 7: 411-425Crossref PubMed Scopus (247) Google Scholar The N-terminal intracellular domain (18-aa) contains a potential protein kinase C phosphorylation site and several nuclear localization sequences.1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar, 9.Marsters S.A. Sheridan J.P. 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Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway.J Biol Chem. 2010; 285: 17432-17441Crossref PubMed Scopus (35) Google Scholar, 7.Nakayama M. Kayagaki N. Yamaguchi N. et al.Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity.J Exp Med. 2000; 192: 1373-1380Crossref PubMed Scopus (123) Google Scholar The intracellular domain of TWEAK contains a furin recognition site, suggesting that full-length TWEAK can be cleaved intracellularly.6.Brown S.A. Ghosh A. Winkles J.A. Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway.J Biol Chem. 2010; 285: 17432-17441Crossref PubMed Scopus (35) Google Scholar Both sTWEAK and mTWEAK bind and activate fibroblast growth factor-inducible-14 (Fn14, TWEAK receptor, TNFRSF12A, CD266)6.Brown S.A. Ghosh A. Winkles J.A. Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway.J Biol Chem. 2010; 285: 17432-17441Crossref PubMed Scopus (35) Google Scholar, 12.Roos C. Wicovsky A. Muller N. et al.Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway.J Immunol. 2010; 185: 1593-1605Crossref PubMed Scopus (39) Google Scholar (Figure 1). Initial reports of TWEAK binding to DR3 (Apo3/TRAMP),9.Marsters S.A. Sheridan J.P. Pitti R.M. et al.Identification of a ligand for the death-domain-containing receptor Apo3.Curr Biol. 1998; 8: 525-528Abstract Full Text Full Text PDF PubMed Google Scholar a TNFRSF member, were not confirmed.7.Nakayama M. Kayagaki N. Yamaguchi N. et al.Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity.J Exp Med. 2000; 192: 1373-1380Crossref PubMed Scopus (123) Google Scholar, 13.Kaptein A. Jansen M. Dilaver G. et al.Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3).FEBS Lett. 2000; 485: 135-141Abstract Full Text Full Text PDF PubMed Google Scholar, 14.Kaplan M.J. Lewis E.E. Shelden E.A. et al.The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.J Immunol. 2002; 169: 6020-6029Crossref PubMed Google Scholar In 2001, Fn14 was found to be the TWEAK receptor.15.Wiley S.R. Cassiano L. Lofton T. et al.A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis.Immunity. 2001; 15: 837-846Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 16.Feng S.L. Guo Y. Factor V.M. et al.The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas.Am J Pathol. 2000; 156: 1253-1261Abstract Full Text Full Text PDF PubMed Google Scholar Fn14 had been described in fibroblasts as a growth factor-regulated, immediate-early response gene.17.Meighan-Mantha R.L. Hsu D.K. Guo Y. et al.The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration.J Biol Chem. 1999; 274: 33166-33176Crossref PubMed Scopus (144) Google Scholar The human Fn14 gene encodes a type I transmembrane protein of 129-aa, which is processed into a mature 102-aa protein. Fn14 is the smallest member of TNFRSF. The extracellular domain (53-aa) contains a cystein-rich domain necessary for TWEAK binding.18.Brown S.A. Richards C.M. Hanscom H.N. et al.The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.Biochem J. 2003; 371: 395-403Crossref PubMed Scopus (110) Google Scholar, 19.He F. Dang W. Saito K. et al.Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily.Protein Sci. 2009; 18: 650-656Crossref PubMed Scopus (13) Google Scholar The intracellular domain (29-aa) does not contain a death domain, thus differing from many TNFRSF members, but contains TNFR-associated factor-binding sites.18.Brown S.A. Richards C.M. Hanscom H.N. et al.The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.Biochem J. 2003; 371: 395-403Crossref PubMed Scopus (110) Google Scholar TWEAK is the only TNFSF member that binds Fn14. There is unconfirmed evidence of the existence of a second TWEAK signaling-transducing receptor. TWEAK induced signal transduction in monocytes/macrophages lacking Fn14.20.Polek T.C. Talpaz M. Darnay B.G. et al.TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor.J Biol Chem. 2003; 278: 32317-32323Crossref PubMed Scopus (116) Google Scholar In addition, CD163 from monocytes lacking Fn14 can also bind TWEAK.21.Bover L.C. Cardo-Vila M. Kuniyasu A. et al.A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications.J Immunol. 2007; 178: 8183-8194Crossref PubMed Google Scholar CD163 could be a TWEAK scavenger, as no TWEAK-induced signaling through CD163 has been observed.21.Bover L.C. Cardo-Vila M. Kuniyasu A. et al.A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications.J Immunol. 2007; 178: 8183-8194Crossref PubMed Google Scholar, 22.Moreno J.A. Munoz-Garcia B. Martin-Ventura J.L. et al.The CD163-expressing macrophages recognize and internalize TWEAK: potential consequences in atherosclerosis.Atherosclerosis. 2009; 207: 103-110Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar TWEAK has multiple functions with potential physiopathological relevance that depend on the microenvironment, the cell type, and the cell state of activation (Figure 2). The basis for these differential responses is poorly understood. TWEAK can regulate cell proliferation, cell death, cell migration, cell differentiation, tissue regeneration, neo-angiogenesis, and inflammation.23.Jakubowski A. Ambrose C. 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Jakubowski A. et al.Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells.Hepatology. 2010; 52: 291-302Crossref PubMed Scopus (61) Google Scholar TWEAK has a role in injury of different organs, including the central nervous system, liver, gut, the vasculature, skeletal muscle, heart, and kidney.29.Mittal A. Bhatnagar S. Kumar A. et al.The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice.J Cell Biol. 2010; 188: 833-849Crossref PubMed Scopus (88) Google Scholar, 34.Tirnitz-Parker J.E. Viebahn C.S. Jakubowski A. et al.Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells.Hepatology. 2010; 52: 291-302Crossref PubMed Scopus (61) Google Scholar, 35.Desplat-Jego S. Creidy R. 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Moreno J.A. et al.TWEAK-Fn14 interaction enhances plasminogen activator inhibitor 1 and tissue factor expression in atherosclerotic plaques and in cultured vascular smooth muscle cells.Cardiovasc Res. 2011; 89: 225-233Crossref PubMed Scopus (23) Google Scholar, 39.Haile W.B. Echeverry R. Wu J. et al.The interaction between tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 promotes the recruitment of neutrophils into the ischemic brain.J Cereb Blood Flow Metab. 2010; 30: 1147-1156Crossref PubMed Scopus (15) Google Scholar However, the precise role of TWEAK in different diseases requires refined characterization, as it may be potentially deleterious or beneficial depending on the context and stage of the disease.8.Winkles J.A. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting.Nat Rev Drug Discov. 2008; 7: 411-425Crossref PubMed Scopus (247) Google Scholar, 40.Burkly L.C. Michaelson J.S. Hahm K. et al.TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease.Cytokine. 2007; 40: 1-16Crossref PubMed Scopus (144) Google Scholar We will review the role of TWEAK/Fn14 in kidney disease. TWEAK, in contrast to other TNFSF cytokines, is broadly expressed and can be found at high levels in the pancreas, intestine, heart, brain, lung, ovary, vasculature, and skeletal muscle, and at lower levels in the liver and kidney.1.Chicheportiche Y. Bourdon P.R. Xu H. et al.TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997; 272: 32401-32410Crossref PubMed Scopus (404) Google Scholar, 9.Marsters S.A. Sheridan J.P. Pitti R.M. et al.Identification of a ligand for the death-domain-containing receptor Apo3.Curr Biol. 1998; 8: 525-528Abstract Full Text Full Text PDF PubMed Google Scholar However, the precise cellular sources of circulating sTWEAK are unclear. Fn14 is expressed by many cell types, including epithelial, mesenchymal, and endothelial cells.40.Burkly L.C. Michaelson J.S. Hahm K. et al.TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease.Cytokine. 2007; 40: 1-16Crossref PubMed Scopus (144) Google Scholar Fn14 expression in healthy tissues, including the kidneys, is usually low, but it is rapidly and highly upregulated in response to injury.15.Wiley S.R. Cassiano L. Lofton T. et al.A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis.Immunity. 2001; 15: 837-846Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 16.Feng S.L. Guo Y. Factor V.M. et al.The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas.Am J Pathol. 2000; 156: 1253-1261Abstract Full Text Full Text PDF PubMed Google Scholar, 23.Jakubowski A. Ambrose C. Parr M. et al.TWEAK induces liver progenitor cell proliferation.J Clin Invest. 2005; 115: 2330-2340Crossref PubMed Scopus (196) Google Scholar, 29.Mittal A. Bhatnagar S. Kumar A. et al.The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice.J Cell Biol. 2010; 188: 833-849Crossref PubMed Scopus (88) Google Scholar, 33.Justo P. Sanz A.B. Sanchez-Nino M.D. et al.Cytokine cooperation in renal tubular cell injury: the role of TWEAK.Kidney Int. 2006; 70: 1750-1758Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 34.Tirnitz-Parker J.E. Viebahn C.S. Jakubowski A. et al.Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells.Hepatology. 2010; 52: 291-302Crossref PubMed Scopus (61) Google Scholar, 35.Desplat-Jego S. Creidy R. 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Sanchez-Nino M.D. Izquierdo M.C. et al.Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.J Cell Mol Med. 2009; 13: 3329-3342Crossref PubMed Scopus (0) Google Scholar Both TWEAK and Fn14 are constitutively expressed at low levels in normal kidneys. Potential local sources of kidney TWEAK include infiltrating monocytes/macrophages and T lymphocytes, and resident cells such as tubular and mesangial cells.7.Nakayama M. Kayagaki N. Yamaguchi N. et al.Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity.J Exp Med. 2000; 192: 1373-1380Crossref PubMed Scopus (123) Google Scholar, 14.Kaplan M.J. Lewis E.E. Shelden E.A. et al.The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.J Immunol. 2002; 169: 6020-6029Crossref PubMed Google Scholar, 33.Justo P. Sanz A.B. Sanchez-Nino M.D. et al.Cytokine cooperation in renal tubular cell injury: the role of TWEAK.Kidney Int. 2006; 70: 1750-1758Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 46.Kim S.H. Kang Y.J. Kim W.J. et al.TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages.Circ J. 2004; 68: 396-399Crossref PubMed Scopus (89) Google Scholar, 47.Molano A. Lakhani P. Aran A. et al.TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis.Immunol Lett. 2009; 125: 119-128Crossref PubMed Scopus (0) Google Scholar Low-level constitutive Fn14 expression is observed in tubular cells, mesangial cells, and podocytes and these cells respond to TWEAK stimulation in culture.33.Justo P. Sanz A.B. Sanchez-Nino M.D. et al.Cytokine cooperation in renal tubular cell injury: the role of TWEAK.Kidney Int. 2006; 70: 1750-1758Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 48.Gao H.X. Campbell S.R. Burkly L.C. et al.TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells.Cytokine. 2009; 46: 24-35Crossref PubMed Scopus (0) Google Scholar TWEAK and Fn14 are constitutively expressed in murine and human renal tubular cells. Basal Fn14 protein levels are low but proinflammatory cytokines quickly (within 2 h) and transitorily increased Fn14 expression.33.Justo P. Sanz A.B. Sanchez-Nino M.D. et al.Cytokine cooperation in renal tubular cell injury: the role of TWEAK.Kidney Int. 2006; 70: 1750-1758Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar The early Fn14 induction in tubular cells is consistent with reports in other cell types.17.Meighan-Mantha R.L. Hsu D.K. Guo Y. et al.The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration.J Biol Chem. 1999; 274: 33166-33176Crossref PubMed Scopus (144) Google Scholar, 49.Munoz-Garcia B. Martin-Ventura J.L. Martinez E. et al.Fn14 is upregulated in cytokine-stimulated vascular smooth muscle cells and is expressed in human carotid atherosclerotic plaques: modulation by atorvastatin.Stroke. 2006; 37: 2044-2053Crossref PubMed Scopus (66) Google Scholar Growth factors present in serum also increase Fn14 expression in tubular cells in a more sustained manner.45.Sanz A.B. Sanchez-Nino M.D. Izquierdo M.C. et al.Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.J Cell Mol Med. 2009; 13: 3329-3342Crossref PubMed Scopus (0) Google Scholar Growth factors also upregulate Fn14 in endothelial cells.50.Donohue P.J. Richards C.M. Brown S.A. et al.TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity.Arterioscler Thromb Vasc Biol. 2003; 23: 594-600Crossref PubMed Scopus (115) Google Scholar The molecular mechanisms that regulate Fn14 expression are not well defined. The Rho/ROCK pathway has been implicated in Fn14 upregulation in human aortic smooth muscle cells and in cardiomyocytes.49.Munoz-Garcia B. Martin-Ventura J.L. Martinez E. et al.Fn14 is upregulated in cytokine-stimulated vascular smooth muscle cells and is expressed in human carotid atherosclerotic plaques: modulation by atorvastatin.Stroke. 2006; 37: 2044-2053Crossref PubMed Scopus (66) Google Scholar, 51.Chorianopoulos E. Heger T. Lutz M. et al.FGF-inducible 14-kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK.Basic Res Cardiol. 2010; 105: 301-313Crossref PubMed Scopus (57) Google Scholar TWEAK expression is upregulated in cultured tubular cells by growth factors from serum.45.Sanz A.B. Sanchez-Nino M.D. Izquierdo M.C. et al.Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.J Cell Mol Med. 2009; 13: 3329-3342Crossref PubMed Scopus (0) Google Scholar It is conceivable that these same factors contribute to constitutive TWEAK or Fn14 expression in vivo. Podocytes and mesangial cells constitutively express TWEAK and Fn14,48.Gao H.X. Campbell S.R. Burkly L.C. et al.TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells.Cytokine. 2009; 46: 24-35Crossref PubMed Scopus (0) Google Scholar, 52.Campbell S. Burkly L.C. Gao H.X. et al.Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells.J Immunol. 2006; 176: 1889-1898Crossref PubMed Google Scholar (unpublished observation). However, the regulation of TWEAK and Fn14 expression in podocytes and mesangial cells has not been studied. A series of reports have highlighted the actions of TWEAK in renal tubular cells, mesangial cells, and podocytes. The identification of signal tr
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