title: Fibrinogen, acting as a mitogen for tubulointerstitial fibroblasts, promotes renal fibrosis.
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.
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors: Inga
authors: I
authors: Sörensen
authors: Nathan
authors: N
authors: Susnik
authors: Therese
authors: T
authors: Inhester
authors: Jay L
authors: JL
authors: Degen
authors: Anette
authors: A
authors: Melk
authors: Herrmann
authors: H
authors: Haller
authors: Roland
authors: R
authors: Schmitt
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C507780:Myd88 protein, mouse; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C464794:fibrinogen Aalpha; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen