Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine, a member of the TNF superfamily, which binds to its cognate receptor fibroblast growth factor-inducible molecule 14 (Fn14) to elicit cellular responses. TWEAK participates in multiple biological processes, including tissue inflammation, repair and regeneration, and has been implicated in a number of complex human diseases, including kidney disease [1,2▪▪]. In this review, we will focus on the recent findings supporting a pathogenic role for TWEAK and its potential as a relevant therapeutic target in renal diseases.
TWEAK AND THE KIDNEY: A POTENTIAL BIOMARKER?
Several studies have focused on soluble TWEAK in the circulation or in urine as a potential biomarker. Initial studies defined soluble TWEAK as a cardiovascular risk biomarker identified by proteomic analysis . Decreased serum soluble TWEAK concentrations were observed in patients with carotid atherosclerosis, coronary artery disease, congestive heart failure and peripheral arterial disease . Decreased soluble TWEAK levels are associated with endothelial dysfunction and predict cardiovascular events in nondialysis chronic kidney disease (CKD), including diabetic and renal transplant patients [2▪▪,4,5]. In contrast, elevated levels of soluble TWEAK predict poor survival in hemodialysis patients and correlate with severe vascular calcification [6,7]. Interestingly, urinary TWEAK levels can be considered as a marker of lupus nephritis activity  and are positively correlated with other urinary biomarkers of this disease .
TWEAK synthesis is a complex process (Fig. 1). TWEAK, as other members of the TNF superfamily, is initially synthesized as a type II transmembrane protein, that is intracellularly processed by the serine protease furin, to release a soluble cytokine . TWEAK mRNA and protein are expressed in many tissues, and TWEAK upregulation has been described in experimental acute renal injury, atherosclerosis and other disorders [1,2▪▪,3]. In contrast, detection of membrane TWEAK by flow cytometry was so far only successful for IFNγ-stimulated monocytes, macrophages, dendritic cells and a few breast cancer cell lines [11▪,12,13]. This points to a strong TWEAK processing activity of furin proteases, although there is also evidence that TWEAK mRNA is inefficiently translated. However, as described above, in CKD circulating soluble TWEAK levels are decreased. Further studies should define the mechanisms regulating soluble TWEAK bioavailability in physiological and pathological conditions. Decreased circulating soluble TWEAK levels could result from receptor-mediated internalization and processing.
Fn14 is the exclusive proven signal-transducing receptor for TWEAK (Fig. 2) . In addition, TWEAK can also bind to the CD163 scavenger receptor in macrophages  (Fig. 2). However, although in this study internalization of TWEAK after binding to CD163 was observed, the functional consequence of this finding and the own ability of TWEAK to interact with CD163 have been recently questioned . Nevertheless, the Fn14 tissue levels are coincidentally upregulated along with the presence of CD163-expressing macrophages in many diseases, thus suggesting that CD163 could be responsible for decreased soluble TWEAK bioavailability in the circulation. This unresolved point should attract future research.
TWEAK-INDUCED CELLULAR RESPONSES: ROLE OF FACTOR-INDUCIBLE MOLECULE 14 RECEPTOR
Both membrane-bound and soluble TWEAK elicit cellular responses after binding to Fn14 (Fig. 2). Fn14 is a type I transmembrane protein belonging to the TNF receptor (TNFR) superfamily but differing from other members of the family by the absence of a death domain in its cytoplasmic tail, whereby TWEAK actions do not mimic those of TNF. Fn14 engagement by TWEAK recruits TNFR-associated factors and activates many intracellular signaling systems, including the transcription factor nuclear factor-κB (NF-κB) and protein kinases, such as the cascade of mitogen-activated protein kinases (MAPKs) [1,2▪▪].
The TWEAK and Fn14 pathway becomes activated specifically in injury and disease contexts, including renal diseases [2▪▪,15]. TWEAK activation of Fn14 regulates several biological responses, such as proinflammatory activity, angiogenesis and cell proliferation, and, under some experimental conditions, apoptosis. Excessive or persistent TWEAK and Fn14 activation drives pathological tissue responses, leading to progressive damage and degeneration [2▪▪,15]. Recent publications have shed new light on the role of TWEAK in renal inflammation and fibrosis and in genitourinary cancer, as we discuss below in detail.
TWEAK, A KEY CYTOKINE IN RENAL INFLAMMATION
Extensive research in cultured renal cells, including glomerular mesangial cells and tubular cells, has demonstrated that TWEAK is an important proinflammatory cytokine (Fig. 3) [2▪▪]. Experimental studies, using pharmacological or genetic approaches, have clearly shown that TWEAK activates Fn14 to induce renal inflammation [2▪▪]. Among the intracellular mechanisms involved in TWEAK-mediated renal inflammation, NF-κB has attracted special interest. TWEAK activates the canonical NF-κB pathway to induce the expression of both soluble and membrane-bound inflammatory chemokines, including MCP-1, RANTES [2▪▪] and CXCL16 [16▪]. TWEAK also activates the noncanonical NF-κB pathway to induce the expression of additional chemokines, such as CCL21 and CCL19 in tubular cells [2▪▪]. TWEAK upregulation of CXCL16 is a recent finding. Transmembrane CXCL16 is an adhesion molecule and behaves as a scavenger receptor for cholesterol. In addition, soluble CXCL16 is a T-cell chemoattractant chemokine. Functional studies demonstrated that TWEAK upregulates CXCL16 in tubular cells in vivo during kidney injury and this is associated with interstitial T-cell infiltrates [16▪].
Although kidney cell Fn14 expression has been shown to be a key element of kidney injury in chimeric mice , TWEAK could also potentially participate in renal inflammation by the direct activation of immune cells (Fig. 3). TWEAK was reported to regulate immune cell functions , although other lines of TWEAK knockout mice did not present such defects . Earlier studies in cardiovascular disease demonstrated that TWEAK activates monocytes contributing to differentiation into macrophages and migration into tissues [1,2▪▪,3]. Unresolved inflammation is a common feature of progressive kidney disease that contributes to chronic tissue damage . Recent studies have highlighted the role of Th17 cells, and their hallmark cytokine interleukin (IL)-17A, in immune-mediated renal disease, as well as in nonimmune inflammatory experimental renal injury, such as unilateral ureteral obstruction (UUO) and ischemia–reperfusion . In naïve murine CD4+ T cells, TWEAK promoted Th17 differentiation . Recent studies suggest that blockade of IL-17A is a promising tool for chronic human inflammatory diseases, such as rheumatoid arthritis, uveitis and psoriasis [21–23], and in experimental renal damage , although there are no data in human renal diseases. In the synovium of rheumatoid arthritis patients, the presence of CD4+ coexpressing IL-17A and Fn14 was found, and Fn14 blockade suppressed Th17 differentiation and, conversely, enhanced Treg differentiation . These data suggest that TWEAK via modulation of the Th17 immune response could also contribute to sustained renal inflammation (Fig. 3), although further research is necessary.
TWEAK AND FIBROSIS
Studies in the cardiovascular field suggest that TWEAK regulates extracellular matrix (ECM) protein production. Earlier data have demonstrated that TWEAK regulates matrix-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, mainly in macrophages [1,2▪▪]. TWEAK and Fn14 blockade modulates fibrosis in the experimental models of cardiac damage [25,26]. Recent studies have evaluated the direct effect of TWEAK on the synthesis of ECM components, such as collagen, the main ECM component in tissue fibrosis. In neonatal rat cardiac fibroblasts, TWEAK increases collagen synthesis by activating the NF-κB pathway and increasing MMP-9 activity . In cardiac fibroblasts, TWEAK induces collagen expression via Fn14–RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A), megakaryocytic acute leukemia protein (MAL) and myocardin-like protein 1 (MKL1) . Activation of Fn14 in vitro caused proliferation of cardiac fibroblasts and differentiation into myofibroblasts . In the liver, TWEAK induces progenitor cell proliferation in vivo. In mice with liver fibrosis, inhibition of progenitor activation using TWEAK-neutralizing antibodies prevents the exaggerated fibrogenic response and improves fibrotic liver regeneration .
There is also evidence for a fibrogenic role of TWEAK and Fn14 in the kidney. In experimental ischemia–reperfusion, an anti-Fn14 blocking antibody diminished initial tubular injury and subsequent residual tubulointerstitial renal fibrosis . However, in this study, the direct effect of Fn14 blockade in the regulation of profibrotic events in renal cells was not evaluated. Fn14 blockade inhibited the production of proinflammatory cytokines and chemokines after ischemia–reperfusion injury, both in vitro and in vivo, suggesting that Fn14 is a critical mediator in the pathogenesis of ischemia–reperfusion injury. In nephrotoxic serum nephritis, an anti-TWEAK neutralizing antibody or Fn14 deficiency resulted in milder tubulointerstitial fibrosis . Again, the effect on residual fibrosis was thought to result from improvement in initial glomerular inflammation.
Indirectly, TWEAK can also regulate fibrosis by modulating cell proliferation. TWEAK expands mesangial cells, which are a source of glomerular ECM production [1,2▪▪]. In cultured murine kidney fibroblasts, TWEAK activated RasGTPases to promote extracellular signal-regulated kinase (ERK)-mediated proliferation and Ras-mediated migration [32▪▪]. Both processes are expected to expand the fibroblast pool and, indeed, this was observed in functional studies in vivo in the model of persistent UUO. By contrast, a direct effect of TWEAK on fibroblasts was to decrease the ECM production in a Ras-dependent and p38 MAPK-dependent manner [32▪▪]. This is consistent with the proliferative effect. Furthermore, TWEAK activated NF-κB-mediated proinflammatory responses in fibroblasts. The integrated result of TWEAK actions on renal fibroblasts was induction of kidney fibrosis in mice with adenovirus-mediated TWEAK overexpression and a reduction of renal fibrosis in UUO TWEAK-deficient mice [32▪▪]. Obstructed TWEAK-deficient kidneys also displayed less tubular injury and interstitial inflammation. These findings are relevant as this is a nonimmune-mediated model and the cause of injury (obstruction) is persistent in contrast to the transient nature of other insults, in which residual renal fibrosis was improved by TWEAK or Fn14 targeting as detailed above.
Importantly, fibrogenic fibroblasts can originate either by proliferation of resident fibroblasts or be derived from multiple parental lineages, including tubular epithelial cells, endothelial cells, bone marrow cells and, as more recently described, from pericytes [33,34▪▪,35]. Another source of myofibroblasts could be the injured renal epithelium by a process known as epithelial-to-mesenchymal transition (EMT) [34▪▪]. However, so far, there are no data about the potential role of TWEAK in the regulation of EMT. Pericytes are also important cells in kidney fibrosis. Under pathogenic conditions, pericytes detach from the vasculature and differentiate into myofibroblasts . The potential actions of TWEAK and Fn14 on pericytes in renal injury should be studied. Circulating fibrocytes may contribute to the kidney fibroblast pool, as demonstrated in the UUO model . Fibrocyte recruitment requires CCL21, a chemokine under TWEAK control .
Finally, TWEAK downregulates the renal expression of the antiaging hormone Klotho . Recently, Klotho was shown to be a potent antikidney fibrosis agent .
Therefore, TWEAK could contribute to renal fibrosis by modulating several processes and eliciting multiple actions on different cell types (Fig. 4), including fibroblast proliferation, tubular cell activation to synthesize proinflammatory mediators, downregulation of antifibrotic molecules or differentiation into fibrogenic myofibroblasts, or acting in other cell types, as pericytes.
TWEAK AND GENITOURINARY CANCER
CKD is complicated by acquired polycystic kidney disease which is, in turn, a preneoplastic lesion. Indeed, CKD is a risk factor for renal cancer . Although there is little information on TWEAK and Fn14 and kidney cancer, a recent report illustrated how manipulation of the system may be used to therapeutically target prostate cancer. Prostate cancer cells express Fn14 [41,42▪]. An early report described prostate cancer cell proliferation and invasion in response to TWEAK . However, in that study prostate cancer cells were cultured in the presence of the survival factors of serum. More recently, it was shown that manipulation of the cell microenvironment could be used to turn the potential advantage of tumors expressing Fn14 into a mode of tumor cell killing. Under an inflammatory microenvironment, serum-deprived, androgen-independent prostate cancer cells underwent apoptosis upon challenge with TWEAK [42▪]. In the light of these results, it might be worth considering the possibility of studying whether kidney cancer follows similar dynamics.
NEW APPROACHES TO TARGET THE DELETERIOUS ACTIONS OF TWEAK
Blockade of TWEAK or Fn14, using genetically modified mice or neutralizing antibodies, ameliorated experimental renal diseases, including lupus nephritis, acute renal injury and nephrotoxic serum nephritis [2▪▪,31,32▪▪]. In this regard, anti-TWEAK blocking antibodies are undergoing clinical trials [2▪▪,44]. A phase I clinical trial was successfully completed (http://clinicaltrials.gov/show/NCT00771329, accessed 02 August 2013) and an ongoing clinical trial, ATLAS (Anti-TWEAK in lupus nephritis patients), is exploring kidney protection in lupus nephritis afforded by neutralizing anti-TWEAK antibodies when conventional immunosuppressive therapy does not result in complete remission within a reasonable period of time (http://clinicaltrials.gov/ct2/show/NCT01499355, accessed 02 August 2013). An improved understanding of TWEAK actions may guide the future development of new therapeutic approaches [2▪▪].
In addition to direct TWEAK and Fn14 targeting, other strategies that block TWEAK and Fn14 signaling and downstream cellular responses could be therapeutic options for CKD. Some recent examples are discussed below.
Polymer therapeutics include the first nanomedicines with proved clinical benefits. Polymers help to stabilize and protect proteins against degradation and also to enhance specific drug delivery into cells, thus improving drug–target interaction [45,46]. A polymer–drug conjugate, polyglutamic acid–peptoid (QM56), which inhibits Apaf-1, apoptosome formation and apoptosis, limits renal damage in murine acute kidney injury [47,48▪▪]. Kidney protection was related to both apoptosis inhibition and to a previously unknown Apaf-1-independent antinflammatory activity. QM56 prevented TWEAK-induced proinflammatory actions on cultured tubular cells by inhibiting TWEAK-dependent NF-κB activation (Fig. 5). QM56 also prevented TWEAK-induced JAK2 activation [48▪▪]. Further structure–function studies should address how to improve QM56-derived polymer therapeutics to treat TWEAK-induced kidney damage.
BLOCKADE OF EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION
Blockade of the epidermal growth factor receptor (EGFR) has been recently suggested as a novel therapeutic option for renal diseases . TWEAK transactivates the EGFR in the kidney and in cultured renal cells [50▪▪]. In astrocytes, long-term TWEAK-mediated cell proliferation is regulated by ERK and EGFR . In renal cells, TNF-α also transactivates EGFR . EGFR transactivation is mediated by ADAM (a disintegrin and metalloproteinase)-dependent EGFR ligand shedding by factors that bind G-protein-coupled receptors. ADAMs involved in EGFR ligand shedding differ for each tissue . In renal cells, TWEAK promotes EGFR transactivation via ADAM17 [50▪▪]. EGFR kinase inhibitors or ADAM17 inhibitors ameliorate experimental renal inflammation induced by systemic TWEAK administration in mice [50▪▪]. These data suggest that EGFR blockade is another therapeutic tool for TWEAK-mediated renal actions.
TWEAK targeting has come of age following a successful phase I clinical trial and the ongoing phase II ATLAS study in lupus nephritis. A successful outcome of the ATLAS trial should spark clinical studies in nonimmune-mediated forms of kidney injury, including acute kidney injury and kidney fibrosis. Even if the trial is not successful, there is a body of preclinical evidence linking TWEAK to kidney injury. Thus, if the trial fails or is not completed, reasons for failure should be clarified. In this regard, novel approaches to target TWEAK actions and fine-tune the modulation of the system should be explored. These include nanomolecules of the QM56 family, EGFR kinase inhibitors and ADAMs inhibitors.
The authors want to thank Sandra Rayego-Mateos for her critical review of the manuscript.
This work was supported by the grants from the Instituto de Salud Carlos III (ISCIIIRETIC REDINREN RD06/0016/0004 and 0003, RD12/0021/0001 and 0002, PI11/0185, PI11/02242, PS09/00447), Comunidad de Madrid (Fibroteam; S2010/BMD-2321, S2010/BMD-2378), Sociedad Española de Nefrología, Research Institute Queen Sophia (FRIAT). ProgramaIntensificaciónActividadInvestigadora (ISCIII/AgenciaLaín-Entralgo/CM) to A.O. Contrato Miguel Servet to A.M.R.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Winkles JA. The TWEAK
-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov 2008; 7:411–425.
2▪▪. Sanz AB, Izquierdo MC, Sanchez-Niño MD, et al. TWEAK
and the progression of renal disease: clinical translation. Nephrol Dial Transplant (in press).
An updated review on the clinical implications of basic research on TWEAK and the kidney with review of ongoing clinical trials targeting TWEAK/Fn14.
3. Blanco-Colio LM, Martín-Ventura JL, Carrero JJ, et al. Vascular proteomics and the discovery process of clinical biomarkers: the case of TWEAK
. Proteomics Clin Appl 2011; 5:281–288.
4. Gungor O, Kismali E, Sisman AR, et al. The relationships between serum sTWEAK, FGF-23 levels, and carotid atherosclerosis in renal transplant patients. Ren Fail 2013; 35:77–81.
5. Llauradó G, González-Clemente JM, Maymó-Masip E, et al. Serum levels of TWEAK
and scavenger receptor CD163 in type 1 diabetes mellitus: relationship with cardiovascular risk factors. A case–control study. PLoS One 2012; 7:e43919.
6. Gungor O, Kircelli F, Asci G, et al. Soluble TWEAK
level: is it a marker for cardiovascular disease in long-term hemodialysis patients? J Nephrol 2013; 26:136–143.
7. Carrero JJ, Ortiz A, Qureshi AR, et al. Additive effects of soluble TWEAK
on mortality in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:110–118.
8. Dhaun N, Kluth DC. TWEAK
: a novel biomarker for lupus nephritis
? Arthritis Res Ther 2009; 11:133–135.
9. El-Shehaby A, Darweesh H, El-Khatib M, et al. Correlations of urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK
), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and IL-8 with lupus nephritis
. J Clin Immunol 2011; 31:848–856.
10. Brown SA, Ghosh A, Winkles JA. Full-length, membrane-anchored TWEAK
can function as a juxtacrine signaling molecule and activate the NF-κB pathway. J Biol Chem 2010; 285:17432–17441.
11▪. Fick A, Lang I, Schäfer V, et al. Studies of binding of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK
) to fibroblast growth factor inducible 14 (Fn14). J Biol Chem 2012; 287:484–495.
A complete biochemical study demonstrating that furin cleaves TWEAK and the functional role of Fn14.
12. Maecker H, Varfolomeev E, Kischkel F, et al. TWEAK
attenuates the transition from innate to adaptive immunity. Cell 2005; 123:931–944.
13. Willis AL, Tran NL, Chatigny JM, et al. The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol Cancer Res 2008; 6:725–734.
14. Moreno JA, Muñoz-García B, Martín-Ventura JL, et al. The CD163-expressing macrophages recognize and internalize TWEAK
: potential consequences in atherosclerosis. Atherosclerosis 2009; 207:103–110.
15. Burkly LC, Michaelson JS, Zheng TS. TWEAK
/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol Rev 2011; 244:99–114.
16▪. Izquierdo MC, Sanz AB, Mezzano S, et al. TWEAK
(tumor necrosis factor-like weak inducer of apoptosis) activates CXCL16 expression during renal tubulointerstitial inflammation
. Kidney Int 2012; 81:1098–1107.
The first time that TWEAK is shown to regulate a multifunctional protein that may behave as cholesterol scavenger receptor, adhesion molecule and chemokine.
17. 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; 125:119–128.
18. Lee SB, Kalluri R. Mechanistic connection between inflammation
. Kidney Int 2010; 78 (Suppl. 119):S22–S26.
19. Kitching AR, Holdsworth SR. The emergence of Th17 cells as effectors of renal injury. J Am Soc Nephrol 2011; 22:235–238.
20. Park JS, Park MK, Lee SY, et al. TWEAK
promotes the production of interleukin-17 in rheumatoid arthritis. Cytokine
21. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2010; 2:52ra72.
22. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012; 366:1190–1199.
23. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366:1181–1189.
24. Rodrigues-Díez R, Rodrigues-Díez RR, Rayego-Mateos S, et al. The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response. Lab Invest 2013; 93:812–824.
25. Jain M, Jakubowski A, Cui L, et al. A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK
) in the development of cardiac dysfunction and failure. Circulation 2009; 119:2058–2068.
26. Novoyatleva T, Schymura Y, Janssen W, et al. Deletion of Fn14 receptor protects from right heart fibrosis
and dysfunction. Basic Res Cardiol 2013; 108:325–337.
27. Chen HN, Wang DJ, Ren MY, et al. TWEAK
/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-кB pathway. Mol Biol Rep 2012; 39:8231–8241.
28. Tirnitz-Parker JE, Viebahn CS, Jakubowski A, et al. Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology 2010; 52:291–302.
29. Kuramitsu K, Sverdlov DY, Liu SB, et al. Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. Am J Pathol 2013; 183:182–194.
30. Hotta K, Sho M, Yamato I, et al. Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury. Kidney Int 2011; 79:179–188.
31. Xia Y, Campbell SR, Broder A, et al. Inhibition of the TWEAK
/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis. Clin Immunol 2012; 145:108–121.
32▪▪. Ucero AC, Benito-Martin A, Fuentes-Calvo I, et al. TNF-related weak inducer of apoptosis (TWEAK
) promotes kidney fibrosis
and Ras-dependent proliferation of cultured renal fibroblast. Biochim Biophys Acta 2013; 1832:1744–1755.
A recent original study exploring in-depth the role of TWEAK in kidney fibrosis when the insult is persistent and delineating the TWEAK actions on renal fibroblast.
33. Ortiz A, Ucero AC, Egido J. Unravelling fibrosis
: two newcomers and an old foe. Nephrol Dial Transplant 2010; 25:3492–3495.
34▪▪. Lebleu VS, Taduri G, O’Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis
. Nat Med 2013; 19:1047–1053.
A recent study demonstrating the role of tubular epithelial cells in renal fibrosis.
35. Campanholle G, Ligresti G, Gharib SA, Duffield JS. Cellular mechanisms of tissue fibrosis
. 3. Novel mechanisms of kidney fibrosis
. Am J Physiol Cell Physiol 2013; 304:C591–C603.
36. Sakai N, Wada T, Yokoyama H, et al. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis
. Proc Natl Acad Sci USA 2006; 103:14098–14103.
37. Sanz AB, Sanchez-Niño MD, Izquierdo MC, et al. TWEAK
activates the noncanonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21. PLoS One 2010; 29:e8955.
38. Moreno JA, Izquierdo MC, Sanchez-Niño MD, et al. The inflammatory cytokines TWEAK
and TNFα reduce renal Klotho expression through NFκB. J Am Soc Nephrol 2011; 22:1315–1325.
39. Sanchez-Niño MD, Sanz AB, Ortiz A. Klotho to treat kidney fibrosis
. J Am Soc Nephrol 2013; 24:687–689.
40. Maisonneuve P, Agodoa L, Gellert R, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999; 10:93–99.
41. Bonsib SM. Renal cystic diseases and renal neoplasms: a mini-review. Clin J Am Soc Nephrol 2009; 4:1998–2007.
42▪. Sanz AB, Sanchez-Niño MD, Carrasco S, et al. Inflammatory cytokines and survival factors from serum modulate TWEAK
-induced apoptosis in PC-3 prostate cancer cells. PLoS One 2012; 7:e47440.
This study explores how altering the tumor cell microenvironment may turn a proliferative response to TWEAK into a lethal signal. It may have application to kidney cancer.
43. Huang M, Narita S, Tsuchiya N, et al. Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome. Carcinogenesis 2011; 32:1589–1596.
44. Michaelson JS, Wisniacki N, Burkly LC, Putterman C. Role of TWEAK
in lupus nephritis
: a bench-to-bedside review. J Autoimmun 2012; 39:130–142.
45. Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov 2003; 2:347–360.
46. Sanchis J, Canal F, Lucas R, Vicent MJ. Polymer drug conjugates for novel molecular targets. Nanomedicine (Lond) 2010; 5:915–935.
47. Vicent MJ, Pérez-Payá E. Poly-L-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J Med Chem 2006; 49:3763–3765.
48▪▪. Ucero AC, Berzal S, Ocaña-Salceda C, et al. A polymeric nanomedicine diminishes inflammatory events in renal tubular cells. PLoS One 2013; 8:e51992.
This study describes the key role of JAK2 in TWEAK-induced inflammation and therapeutic modulation of TWEAK-elicited responses by the nanomolecule QM-56.
49. Flamant M, Bollée G, Hénique C, Tharaux PL. Epidermal growth factor: a new therapeutic target in glomerular disease. Nephrol Dial Transplant 2012; 27:1297–1304.
50▪▪. Rayego-Mateos S, Morgado-Pascual JL, Sanz AB, et al. TWEAK
transactivation of the epidermal growth factor receptor mediates renal inflammation
. J Pathol 2013; 231:480–494.
A recent finding showing a novel mechanism involved in TWEAK-mediated renal inflammation, the activation of the EGFR pathway, which is independent of NF-κB activation.
51. Rousselet E, Traver S, Monnet Y, et al. Tumor necrosis factor-like weak inducer of apoptosis induces astrocyte proliferation through the activation of transforming-growth factor-α/epidermal growth factor receptor signaling pathway. Mol Pharmacol 2012; 82:948–957.
52. Kakiashvili E, Dan Q, Vandermeer M, et al. The epidermal growth factor receptor mediates tumor necrosis factor-alpha-induced activation of the ERK/GEF-H1/RhoA pathway in tubular epithelium. J Biol Chem 2011; 286:9268–9279.