title: Recombinant N-Terminal Slit2 Inhibits TGF-β-Induced Fibroblast Activation and Renal Fibrosis.
abstract: Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-β Here, we examined whether Slit2 also controls TGF-β-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-β-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis.
authors: Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and.
authors: Darren A
authors: DA
authors: Yuen
authors: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors: Yi-Wei
authors: YW
authors: Huang
authors: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors: Guang-Ying
authors: GY
authors: Liu
authors: Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors: Sajedabanu
authors: S
authors: Patel
authors: Division of Nephrology and.
authors: Fei
authors: F
authors: Fang
authors: Division of Nephrology and.
authors: Joyce
authors: J
authors: Zhou
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Kerri
authors: K
authors: Thai
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Ahmad
authors: A
authors: Sidiqi
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Stephen G
authors: SG
authors: Szeto
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Lauren
authors: L
authors: Chan
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Mingliang
authors: M
authors: Lu
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada;
authors: Xiaolin
authors: X
authors: He
authors: Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada.
authors: Rohan
authors: R
authors: John
authors: Keenan Research Centre of Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and.
authors: Richard E
authors: RE
authors: Gilbert
authors: Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and Division of Nephrology and.
authors: James W
authors: JW
authors: Scholey
authors: Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and lisa.robinson@sickkids.ca.
authors: Lisa A
authors: LA
authors: Robinson
mesh_terms: D000818:Animals; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology*; D005355:Fibrosis / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000098552:Slit Homolog 2 Protein
keywords: Robo; Slit2; Transforming growth factor-beta; fibrosis