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• W2024694557 abstract "Fibrinogen plays an important role in blood coagulation but its function extends far beyond blood clotting being involved in inflammation and repair. Besides these crucial functions it can also promote tissue fibrosis. To determine whether fibrinogen is involved in the development of renal tubulointerstitial fibrosis we utilized the profibrotic model of unilateral ureteral obstruction in fibrinogen-deficient mice. In the heterozygotes, obstruction was associated with a massive deposition of intrarenal fibrinogen. Fibrinogen deficiency provided significant protection from interstitial damage and tubular disruption, attenuated collagen accumulation, and greatly reduced de novo expression of α-smooth muscle actin in the obstructed kidney. While no differences were found in renal inflammatory cell infiltration, fibrinogen deficiency was associated with a significant reduction in interstitial cell proliferation, a hallmark of renal fibrosis. In vitro, fibrinogen directly stimulated renal fibroblast proliferation in a dose-dependent manner. This mitogenic effect of fibrinogen was mediated by at least three different cell surface receptors on renal fibroblasts: TLR2, TLR4, and ICAM-1. Thus, our study suggests that fibrinogen promotes renal fibrosis by triggering resident fibroblast proliferation. Fibrinogen plays an important role in blood coagulation but its function extends far beyond blood clotting being involved in inflammation and repair. Besides these crucial functions it can also promote tissue fibrosis. To determine whether fibrinogen is involved in the development of renal tubulointerstitial fibrosis we utilized the profibrotic model of unilateral ureteral obstruction in fibrinogen-deficient mice. In the heterozygotes, obstruction was associated with a massive deposition of intrarenal fibrinogen. Fibrinogen deficiency provided significant protection from interstitial damage and tubular disruption, attenuated collagen accumulation, and greatly reduced de novo expression of α-smooth muscle actin in the obstructed kidney. While no differences were found in renal inflammatory cell infiltration, fibrinogen deficiency was associated with a significant reduction in interstitial cell proliferation, a hallmark of renal fibrosis. In vitro, fibrinogen directly stimulated renal fibroblast proliferation in a dose-dependent manner. This mitogenic effect of fibrinogen was mediated by at least three different cell surface receptors on renal fibroblasts: TLR2, TLR4, and ICAM-1. Thus, our study suggests that fibrinogen promotes renal fibrosis by triggering resident fibroblast proliferation. The primary role of the coagulation system is to prevent blood loss after vascular injury by ensuring the formation of stable hemostatic clots. However, the function of the coagulation system extends far beyond blood clotting, including such diverse processes as protection against infection, inflammation, and tissue repair.1.Clark R.A. Fibrin is a many splendored thing.J Invest Dermatol. 2003; 121: xxi-xxiiAbstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,2.Laurens N. Koolwijk P. de Maat M.P. Fibrin structure and wound healing.J Thromb Haemost. 2006; 4: 932-939Crossref PubMed Scopus (473) Google Scholar Some of these effects have specifically been linked to fibrinogen.3.Flick M.J. LaJeunesse C.M. Talmage K.E. et al.Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.J Clin Invest. 2007; 117: 3224-3235Crossref PubMed Scopus (131) Google Scholar, 4.Paul J. Strickland S. Melchor J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease.J Exp Med. 2007; 204: 1999-2008Crossref PubMed Scopus (237) Google Scholar, 5.Drew A.F. Liu H. Davidson J.M. et al.Wound-healing defects in mice lacking fibrinogen.Blood. 2001; 97: 3691-3698Crossref PubMed Scopus (170) Google Scholar Fibrinogen is found in plasma at a concentration of 1.5–4.5g/l and consists of two identical subunits that contain three polypeptide chains: α, β, and γ.2.Laurens N. Koolwijk P. de Maat M.P. Fibrin structure and wound healing.J Thromb Haemost. 2006; 4: 932-939Crossref PubMed Scopus (473) Google Scholar Cleavage by thrombin releases fibrinopeptides A and B and converts fibrinogen into fibrin. Activation of the coagulation cascade and the deposition of fibrin into the provisional extracellular matrix is an integral part of tissue injury. The fibrin-containing matrix can promote infiltration of repair cells and can activate healing mechanisms such as angiogenesis, reepithelialization, cell proliferation, and wound contraction.1.Clark R.A. Fibrin is a many splendored thing.J Invest Dermatol. 2003; 121: xxi-xxiiAbstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar However, if imbalanced, these wound-healing mechanisms can contribute to excessive scar formation and organ fibrosis. Gene-targeting studies suggest that fibrinogen might play a role in tipping the balance between healthy wound-healing and fibrotic scarring.6.de Giorgio-Miller A. Bottoms S. Laurent G. et al.Fibrin-induced skin fibrosis in mice deficient in tissue plasminogen activator.Am J Pathol. 2005; 167: 721-732Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Consistent with this hypothesis, fibrinogen has been demonstrated to promote the development of fibrosis in several organs including pancreas, skin, and muscle.6.de Giorgio-Miller A. Bottoms S. Laurent G. et al.Fibrin-induced skin fibrosis in mice deficient in tissue plasminogen activator.Am J Pathol. 2005; 167: 721-732Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 7.Masamune A. Kikuta K. Watanabe T. et al.Fibrinogen induces cytokine and collagen production in pancreatic stellate cells.Gut. 2009; 58: 550-559Crossref PubMed Scopus (88) Google Scholar, 8.Vidal B. Serrano A.L. Tjwa M. et al.Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway.Genes Dev. 2008; 22: 1747-1752Crossref PubMed Scopus (181) Google Scholar In the kidney, progressive fibrosis is the final pathway of most chronic diseases leading to irreversible loss of renal function.9.Hewitson T.D. Renal tubulointerstitial fibrosis: common but never simple.Am J Physiol Renal Physiol. 2009; 296: F1239-F1244Crossref PubMed Scopus (204) Google Scholar Fibrinogen might be a novel candidate molecule in the development of renal fibrosis given the above-mentioned results from other organs. Massive fibrin deposition is commonly observed in renal biopsies in a variety of acute and chronic kidney diseases,10.Kincaid-Smith P. Coagulation and renal disease.Kidney Int. 1972; 2: 183-190Abstract Full Text PDF PubMed Scopus (131) Google Scholar, 11.Bruno N.E. Yano Y. Takei Y. et al.Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency.Thromb Haemost. 2008; 100: 90-100PubMed Google Scholar, 12.Shin J.I. Park J.M. Shin Y.H. et al.Role of mesangial fibrinogen deposition in the pathogenesis of crescentic Henoch-Schonlein nephritis in children.J Clin Pathol. 2005; 58: 1147-1151Crossref PubMed Scopus (14) Google Scholar and experimentally it has been shown that the lack of fibrinogen can attenuate renal impairment in inflammatory glomerulonephritis.13.Drew A.F. Tucker H.L. Liu H. et al.Crescentic glomerulonephritis is diminished in fibrinogen-deficient mice.Am J Physiol Renal Physiol. 2001; 281: F1157-F1163Crossref PubMed Scopus (72) Google Scholar Therefore, the aim of this study was to address the hypothesis that fibrinogen plays a direct role in the development and progression of renal fibrosis. To test the impact of fibrinogen on renal fibrosis, kidneys from fibrinogen knock-out (Fib−/−) and heterozygous (Fib+/−) mice were compared at 1 or 2 weeks of unilateral ureteral obstruction (UUO). It was found that the lack of fibrinogen was associated with a significant protection from developing tubulointerstitial damage. UUO kidneys from Fib−/− mice showed significantly less deposition of extracellular matrix and greatly attenuated expansion of resident fibroblasts. In vitro, fibrinogen stimulated renal fibroblast proliferation directly, which was mediated by at least three different cell surface receptors. Consistent with published data by Yamaguchi et al.,14.Yamaguchi I. Lopez-Guisa J.M. Cai X. et al.Endogenous urokinase lacks antifibrotic activity during progressive renal injury.Am J Physiol Renal Physiol. 2007; 293: F12-F19Crossref PubMed Scopus (33) Google Scholar we observed a more than tenfold increase of fibrinogen by immunoblot in UUO kidneys from wild-type mice after 7 days of ureteral obstruction (Figure 1a). Immunoreactivity recognizing both fibrinogen and fibrin was restricted to the intravascular space in contralateral kidneys, whereas it was massively enhanced in the tubulointerstitial space of UUO kidneys (Figure 1b and c). To test whether fibrinogen would contribute to the development of renal fibrosis, Fib−/− mice were subjected to UUO and compared with heterozygous littermates. Fib−/− mice had a normal phenotype under baseline conditions and no appreciable increase in bleeding risk or healing defects after UUO surgery. At day 14 of obstruction, kidneys from Fib+/− animals exhibited fibrinogen deposits throughout the entire renal interstitium (Figure 1d and e). In some areas we found particularly intense accumulations, which was often associated with increased tubulointerstitial damage (Figure 1d). As expected, we found no fibrinogen in kidneys from Fib−/− mice (Figure 1f). At day 7 of UUO, both groups showed dilated tubules with flattened epithelium and a mild increase in interstitial volume without histologically appreciable differences (Figure 1g–i). At 14 days, however, loss of tubular structures and expansion of interstitial cells and matrix was significantly more severe in Fib+/− when compared with Fib−/− mice (Figure 1i–k). Whereas tubules were often replaced by fibrous tissue in Fib+/− kidneys, tubular structures persisted significantly longer in Fib−/− mice (Figure 1j–m). We consistently found a significant reduction in intrarenal collagen deposition in Fib−/− mice as shown by Picrosirius Red staining (Figure 2a and b) and immunoblot (Figure 2c).Figure 2Fibrinogen deficiency is associated with reduced collagen accumulation. (a, a’) Representative microphotographs of collagen deposition as visualized by Picrosirius Red staining using (a) light microscopy and (a’) polarized light at 14 days of unilateral ureteral obstruction (UUO). (b) Quantification of Picrosirius Red polarized images in cortex and outer medulla (OM). (c) Immunoblot analysis for Collagen I using Fib+/− and Fib−/− kidneys at 14 days of UUO. (d) Representative microphotographs of immunostaining for CD45. (e) Quantification of CD45-positive leukocytes, CD4-positive lymphocytes, F4/80-positive macrophages, and Ly-6B.2-positive polymorphonuclear cells in UUO kidneys at 7 and/or 14 days of UUO. Original magnification × 400 (a, a’, d). Scale bars represent mean values±s.e.m. *P<0.05; **P<0.01.View Large Image Figure ViewerDownload (PPT) Although their role is not completely understood,15.Eddy A.A. Serine proteases, inhibitors and receptors in renal fibrosis.Thromb Haemost. 2009; 101: 656-664Crossref PubMed Scopus (68) Google Scholar inflammatory cells infiltrating the interstitium are characteristic features of renal fibrosis. Consistently, increased numbers of infiltrating CD45-positive leukocytes, CD4-positive lymphocytes, F4/80-positive macrophages, and Ly-6B.2-positive polymorphonuclear cells were found in UUO kidneys of both groups. Fibrinogen deficiency however, had no impact on the respective cell counts (Figure 2d and e). α-Smooth muscle actin (α-SMA), which is used as a marker of myofibroblasts,9.Hewitson T.D. Renal tubulointerstitial fibrosis: common but never simple.Am J Physiol Renal Physiol. 2009; 296: F1239-F1244Crossref PubMed Scopus (204) Google Scholar was significantly upregulated in the tubulointerstitial space of UUO kidneys from both groups. However, the upregulation was significantly higher in Fib+/− animals when compared with Fib−/− littermates (Figure 3a and b). For further analysis of differences in interstitial cell expansion, immunostainings using S100A4 were performed, showing a massive increase in S100A4-positive cells in Fib+/− when compared with Fib−/− kidneys (Supplementary Figure S1B online). S100A4 is widely used as a marker for fibroblasts and myofibroblasts,16.Iwano M. Plieth D. Danoff T.M. et al.Evidence that fibroblasts derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (1715) Google Scholar but its specificity has been questioned because of expression by inflammatory cells.17.Le Hir M. Hegyi I. Cueni-Loffing D. et al.Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys.Histochem Cell Biol. 2005; 123: 335-346Crossref PubMed Scopus (113) Google Scholar We therefore quantified only those S100A4-positive cells that were CD45 negative (Figure 3c–e), and found that fibrinogen deficiency was associated with significantly lower numbers of S100A4+/CD45- cells after 7 and 14 days of UUO (Figure 3e). These results were further confirmed by using ER-TR7, an independent fibroblast marker18.Tsujie M. Isaka Y. Ando Y. et al.Gene transfer targeting interstitial fibroblasts by the artificial viral envelope-type hemagglutinating virus of Japan liposome method.Kidney Int. 2000; 57: 1973-1980Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar (Figure 3f and g), and suggest a differential expansion of the interstitial fibroblast population as a possible mechanism for the profibrogenic effects of fibrinogen. Download .jpg (.15 MB) Help with files Supplementary Figure 1 Proliferation of interstitial fibroblasts has been identified as a leading mechanism in progressive renal fibrosis.19.Grgic I. Kiss E. Kaistha B.P. et al.Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels.Proc Natl Acad Sci USA. 2009; 106: 14518-14523Crossref PubMed Scopus (135) Google Scholar,20.Picard N. Baum O. Vogetseder A. et al.Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat.Histochem Cell Biol. 2008; 130: 141-155Crossref PubMed Scopus (129) Google Scholar In agreement with this, we found a high rate of proliferation in interstitial fibroblasts in UUO kidneys from both groups. However, staining for cell cycling marker Ki67 exhibited significantly lower rates of interstitial cell proliferation in Fib−/− kidneys when compared with Fib+/− kidneys after 7 and 14 days (Figure 4a). In contrast, no difference was observed in the number of proliferating tubular epithelial cells between the groups (Supplementary Figure S1C online). These findings suggest that fibrinogen exerts a profibrogenic effect by enhancing the proliferation of interstitial fibroblasts. It has been previously demonstrated that fibrinogen is a mitogen for some cell types21.Gardiner E.E. D’Souza S.E. A mitogenic action for fibrinogen mediated through intercellular adhesion molecule-1.J Biol Chem. 1997; 272: 15474-15480Crossref PubMed Scopus (44) Google Scholar but not for others.7.Masamune A. Kikuta K. Watanabe T. et al.Fibrinogen induces cytokine and collagen production in pancreatic stellate cells.Gut. 2009; 58: 550-559Crossref PubMed Scopus (88) Google Scholar Using normal rat kidney interstitial fibroblasts (NRK-49F cells), we found that exposure to fibrinogen significantly increased cell proliferation in a dose-dependent manner (Figure 4b). This effect was cell-type specific, as no changes in proliferation were observed in renal epithelial cells (mPT and IMCD3 cells; Supplementary Figure S1D and E online). To substantiate the observed effect, we exposed renal fibroblasts to plasma from Fib−/− and Fib+/− mice. Consistent with the first results, we found a significantly stronger proliferation using fibrinogen-containing plasma when compared with fibrinogen-free plasma (Figure 4c). Collectively, these in vitro data indicate that fibrinogen acts as a direct mitogen on renal interstitial fibroblasts. The transition of resting fibroblasts into active α-SMA-positive myofibroblasts is regarded as a critical event in renal fibrosis progression.9.Hewitson T.D. Renal tubulointerstitial fibrosis: common but never simple.Am J Physiol Renal Physiol. 2009; 296: F1239-F1244Crossref PubMed Scopus (204) Google Scholar In order to test whether fibrinogen promotes the transition of fibroblasts to activated myofibroblasts, we evaluated the fibrinogen-dependent de novo expression of α-SMA and fibronectin. After fibrinogen exposure, we found no significant induction of α-SMA or increase in fibronectin on protein (Figure 4d) or mRNA level (data not shown). Thus, these results argue against a significant role for fibrinogen in the conversion from fibroblasts to myofibroblasts, but suggest an increase in the pool of interstitial fibroblasts as the leading mechanism. The activation into myofibroblasts requires the presence of additional factors that are characteristic of UUO such as transforming growth factor-β. Fibrinogen can interact with a variety of cell surface receptors that are known to be expressed on fibroblasts.2.Laurens N. Koolwijk P. de Maat M.P. Fibrin structure and wound healing.J Thromb Haemost. 2006; 4: 932-939Crossref PubMed Scopus (473) Google Scholar Among these, the integrin receptor family and the according downstream signaling have a well-described role in renal fibrosis.22.Hao S. Shen H. Hou Y. et al.tPA is a potent mitogen for renal interstitial fibroblasts: role of beta1 integrin/focal adhesion kinase signaling.Am J Pathol. 2010; 177: 1164-1175Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,23.Li Y. Tan X. Dai C. et al.Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis.J Am Soc Nephrol. 2009; 20: 1907-1918Crossref PubMed Scopus (99) Google Scholar However, treatment with RGD (arginine–glycine–aspartic acid)-containing peptides or β1-integrin antibody had no significant impact on fibrinogen-induced proliferation (Supplementary Figure S1F online). We therefore focused on the Toll-like receptor (TLR) family that has been shown to play a crucial role in the progression of renal fibrosis.24.Pulskens W.P. Rampanelli E. Teske G.J. et al.TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury.J Am Soc Nephrol. 2010; 21: 1299-1308Crossref PubMed Scopus (127) Google Scholar, 25.Campbell M.T. Hile K.L. Zhang H. et al.Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis.J Surg Res. 2009Google Scholar, 26.Anders H.J. Toll-like receptors and danger signaling in kidney injury.J Am Soc Nephrol. 2010; 21: 1270-1274Crossref PubMed Scopus (107) Google Scholar Fibrinogen is a known ligand for TLR2 and TLR4 that are both expressed on renal fibroblasts.27.Smiley S.T. King J.A. Hancock W.W. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4.J Immunol. 2001; 167: 2887-2894Crossref PubMed Scopus (787) Google Scholar, 28.Pierer M. Rethage J. Seibl R. et al.Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands.J Immunol. 2004; 172: 1256-1265Crossref PubMed Scopus (210) Google Scholar, 29.Leemans J.C. Butter L.M. Pulskens W.P. et al.The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.PLoS One. 2009; 4: e5704Crossref PubMed Scopus (107) Google Scholar Specific small interfering RNA (siRNA) knockdown of TLR2 and TLR4 (knockdown efficiency of 87 and 79%, respectively; Supplementary Figure S1G online) resulted in a significant reduction in the mitogenic potential of fibrinogen (Figure 5a). Similarly, siRNA knockdown of myeloid differentiation primary-response gene 88 (MyD88), which is the signaling adaptor shared by TLR2 and TLR4,26.Anders H.J. Toll-like receptors and danger signaling in kidney injury.J Am Soc Nephrol. 2010; 21: 1270-1274Crossref PubMed Scopus (107) Google Scholar resulted in significantly reduced proliferation (Figure 5b; siRNA knockdown efficiency of 76%; Supplementary Figure S1G online). These data were confirmed in primary renal fibroblasts from MyD88 knockout mice displaying a blunted mitogenic effect after fibrinogen exposure when compared with wild-type fibroblasts (Figure 5c). Although these results demonstrate an important role for TLR-dependent signaling, the inhibition of proliferation was only partial, suggesting additional pathways of mitogenic activation. We therefore investigated the role of another cell surface receptor, intercellular adhesion molecule 1 (ICAM-1), that has previously been shown to mediate fibrinogen-induced proliferation in lymphoma cells21.Gardiner E.E. D’Souza S.E. A mitogenic action for fibrinogen mediated through intercellular adhesion molecule-1.J Biol Chem. 1997; 272: 15474-15480Crossref PubMed Scopus (44) Google Scholar and that has been implied in tissue fibrosis.30.Matsushita Y. Hasegawa M. Matsushita T. et al.Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice.J Immunol. 2007; 179: 698-707Crossref PubMed Scopus (32) Google Scholar After confirming a strong expression of ICAM-1 in rat renal fibroblasts (Supplementary Figure S1H online), we used blocking antibodies to ICAM-1 that showed a significant attenuation of the proliferative effect of fibrinogen (Figure 5d). This observation was corroborated in siRNA-based ICAM-1 knockdown experiments (Figure 5e; siRNA knockdown efficiency of 68%; Supplementary Figure S1G online). The antimitogenic effects of TLR2, TLR4, and ICAM-1 knockdown were additive, as shown by combined siRNA experiments (Figure 5e). Taken together, these data suggest that fibrinogen is involved in renal fibroblast proliferation through TLR2-, TLR4-, and ICAM-1-dependent signaling. In this report, we propose a novel mechanism in which fibrinogen or its derivatives promote renal fibrosis by enhancing renal fibroblast proliferation. This mechanism is consistent with the concept that an enhanced proliferation of resident interstitial fibroblasts represents a major driving force in progressive renal fibrosis.19.Grgic I. Kiss E. Kaistha B.P. et al.Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels.Proc Natl Acad Sci USA. 2009; 106: 14518-14523Crossref PubMed Scopus (135) Google Scholar,20.Picard N. Baum O. Vogetseder A. et al.Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat.Histochem Cell Biol. 2008; 130: 141-155Crossref PubMed Scopus (129) Google Scholar Genetic ablation of fibrinogen was associated with a significantly reduced proliferation of interstitial fibroblasts and attenuated renal damage. An important role in the development of tissue fibrosis has been demonstrated for different components of the coagulation system.15.Eddy A.A. Serine proteases, inhibitors and receptors in renal fibrosis.Thromb Haemost. 2009; 101: 656-664Crossref PubMed Scopus (68) Google Scholar,31.Ruppert C. Markart P. Wygrecka M. et al.Role of coagulation and fibrinolysis in lung and renal fibrosis.Hamostaseologie. 2008; 28 (34-36): 30-32PubMed Google Scholar In order to dissociate the function of fibrinogen as a coagulation protein from its potential function as a proproliferating factor, we performed in vitro experiments in the absence of other coagulation components. In vitro, fibrinogen acted as a strong mitogen, promoting renal fibroblast expansion. Fibrinogen exerted its mitogenic effect through at least three different receptors: TLR2, TLR4, and ICAM-1. Fibrinogen binding to ICAM-1 has previously been shown to regulate various physiological and pathophysiological processes, such as cardiomyocyte contractility,32.Boyd J.H. Chau E.H. Tokunanga C. et al.Fibrinogen decreases cardiomyocyte contractility through an ICAM-1-dependent mechanism.Crit Care. 2008; 12: R2Crossref PubMed Scopus (25) Google Scholar lymphocyte proliferation,21.Gardiner E.E. D’Souza S.E. A mitogenic action for fibrinogen mediated through intercellular adhesion molecule-1.J Biol Chem. 1997; 272: 15474-15480Crossref PubMed Scopus (44) Google Scholar and endothelial permeability.33.Patibandla P.K. Tyagi N. Dean W.L. et al.Fibrinogen induces alterations of endothelial cell tight junction proteins.J Cell Physiol. 2009; 221: 195-203Crossref PubMed Scopus (55) Google Scholar Interestingly, it has been shown that ICAM-1 is highly upregulated in UUO34.Ramila D. Ardura J.A. Esteban V. et al.Parathyroid hormone-related protein promotes inflammation in the kidney with an obstructed ureter.Kidney Int. 2008; 73: 835-847Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar and that its deficiency is associated with a striking reduction in renal fibrosis progression in models of diabetic nephropathy and nephrotoxic nephritis.35.Chow F.Y. Nikolic-Paterson D.J. Ozols E. et al.Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice.J Am Soc Nephrol. 2005; 16: 1711-1722Crossref PubMed Scopus (237) Google Scholar,36.Janssen U. Ostendorf T. Gaertner S. et al.Improved survival and amelioration of nephrotoxic nephritis in intercellular adhesion molecule-1 knockout mice.J Am Soc Nephrol. 1998; 9: 1805-1814PubMed Google Scholar Although this protective effect of ICAM-1 deletion has been mainly attributed to an attenuated recruitment of inflammatory cells, our data suggest that decreased fibroblast proliferation might have played an additional role. The TLR family, which was originally identified as a defense mechanism against invasion of pathogenic microorganisms, is increasingly recognized to play an important role in a variety of acute and chronic renal diseases.26.Anders H.J. Toll-like receptors and danger signaling in kidney injury.J Am Soc Nephrol. 2010; 21: 1270-1274Crossref PubMed Scopus (107) Google Scholar Fibrinogen is a prominent nonpathogen-derived TLR activator that has been shown to induce diverse biological effects through binding to TLR2 and TLR4.27.Smiley S.T. King J.A. Hancock W.W. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4.J Immunol. 2001; 167: 2887-2894Crossref PubMed Scopus (787) Google Scholar,37.Motojima M. Matsusaka T. Kon V. et al.Fibrinogen that appears in Bowman's space of proteinuric kidneys in vivo activates podocyte Toll-like receptors 2 and 4 in vitro.Nephron Exp Nephrol. 2010; 114: e39-e47Crossref PubMed Scopus (30) Google Scholar A large body of evidence underlines a crucial role for TLRs in promoting acute and chronic injury responses in the kidney.26.Anders H.J. Toll-like receptors and danger signaling in kidney injury.J Am Soc Nephrol. 2010; 21: 1270-1274Crossref PubMed Scopus (107) Google Scholar,38.Gluba A. Banach M. Hannam S. et al.The role of Toll-like receptors in renal diseases.Nat Rev Nephrol. 2010; 6: 224-235Crossref PubMed Scopus (159) Google Scholar However, recent data have been conflicting with regard to the specific implications of TLR2 and TLR4 in promoting renal fibrosis.24.Pulskens W.P. Rampanelli E. Teske G.J. et al.TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury.J Am Soc Nephrol. 2010; 21: 1299-1308Crossref PubMed Scopus (127) Google Scholar,25.Campbell M.T. Hile K.L. Zhang H. et al.Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis.J Surg Res. 2009Google Scholar,29.Leemans J.C. Butter L.M. Pulskens W.P. et al.The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.PLoS One. 2009; 4: e5704Crossref PubMed Scopus (107) Google Scholar,39.Chowdhury P. Sacks S.H. Sheerin N.S. Endogenous ligands for TLR2 and TLR4 are not involved in renal injury following ureteric obstruction.Nephron Exp Nephrol. 2010; 115: e122-e130Crossref PubMed Scopus (16) Google Scholar Our results are consistent with two studies showing that TLR4-deficient mice are protected from developing renal fibrosis in UUO.24.Pulskens W.P. Rampanelli E. Teske G.J. et al.TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury.J Am Soc Nephrol. 2010; 21: 1299-1308Crossref PubMed Scopus (127) Google Scholar,25.Campbell M.T. Hile K.L. Zhang H. et al.Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis.J Surg Res. 2009Google Scholar Although most previous studies have related TLR-dependent effects in renal injury to renal epithelial cells and to infiltrating immune cells, our data suggest a hitherto unrecognized role for TLR-dependent signaling in the fibroblast population. Interestingly, fibrinogen deficiency had no appreciable effect on renal leukocyte infiltration in our model of UUO. This finding was unexpected, given the ample data on proinflammatory properties of fibrinogen.2.Laurens N. Koolwijk P. de Maat M.P. Fibrin structure and wound healing.J Thromb Haemost. 2006; 4: 932-939Crossref PubMed Scopus (473) Google Scholar, 3.Flick M.J. LaJeunesse C.M. Talmage K.E. et al.Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.J Clin Invest. 2007; 117: 3224-3235Crossref PubMed Scopus (131) Google Scholar, 4.Paul J. Strickland S. Melchor J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease.J Exp Med." @default.
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• W2024694557 title "Fibrinogen, acting as a mitogen for tubulointerstitial fibroblasts, promotes renal fibrosis" @default.
• W2024694557 cites W1613884642 @default.
• W2024694557 cites W1720454525 @default.
• W2024694557 cites W1787909067 @default.
• W2024694557 cites W1813989204 @default.
• W2024694557 cites W1870536856 @default.
• W2024694557 cites W1965218579 @default.
• W2024694557 cites W1966750273 @default.
• W2024694557 cites W1968586704 @default.
• W2024694557 cites W1983651055 @default.
• W2024694557 cites W1991054742 @default.
• W2024694557 cites W2000917871 @default.
• W2024694557 cites W2002026389 @default.
• W2024694557 cites W2007042133 @default.
• W2024694557 cites W2010936139 @default.
• W2024694557 cites W2021843623 @default.
• W2024694557 cites W2042810517 @default.
• W2024694557 cites W2046809665 @default.
• W2024694557 cites W2057368294 @default.
• W2024694557 cites W2061853640 @default.
• W2024694557 cites W2068428035 @default.
• W2024694557 cites W2068440683 @default.
• W2024694557 cites W2077173577 @default.
• W2024694557 cites W2088734429 @default.
• W2024694557 cites W2090591357 @default.
• W2024694557 cites W2096796626 @default.
• W2024694557 cites W2097975125 @default.
• W2024694557 cites W2099079080 @default.
• W2024694557 cites W2107277218 @default.
• W2024694557 cites W2110905507 @default.
• W2024694557 cites W2119136249 @default.
• W2024694557 cites W2124572189 @default.
• W2024694557 cites W2129247391 @default.
• W2024694557 cites W2130104463 @default.
• W2024694557 cites W2130186203 @default.
• W2024694557 cites W2134517037 @default.
• W2024694557 cites W2141365440 @default.
• W2024694557 cites W2142154499 @default.
• W2024694557 cites W2145280913 @default.
• W2024694557 cites W2148070218 @default.
• W2024694557 cites W2150697205 @default.
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