title: Protein-bound uremic toxins induce tissue remodeling by targeting the EGF receptor.
abstract: Indoxyl sulfate and p-cresol sulfate have been suggested to induce kidney tissue remodeling. This study aimed to clarify the molecular mechanisms underlying this tissue remodeling using cultured human proximal renal tubular cells and half-nephrectomized mice treated with indoxyl sulfate or p-cresol sulfate as study models. Molecular docking results suggested that indoxyl sulfate and p-cresol sulfate dock on a putative interdomain pocket of the extracellular EGF receptor. In vitro spectrophotometric analysis revealed that the presence of a synthetic EGF receptor peptide significantly decreased the spectrophotometric absorption of indoxyl sulfate and p-cresol sulfate. In cultured cells, indoxyl sulfate and p-cresol sulfate activated the EGF receptor and downstream signaling by enhancing receptor dimerization, and increased expression of matrix metalloproteinases 2 and 9 in an EGF receptor-dependent manner. Treatment of mice with indoxyl sulfate or p-cresol sulfate significantly activated the renal EGF receptor and increased the tubulointerstitial expression of matrix metalloproteinases 2 and 9. In conclusion, indoxyl sulfate and p-cresol sulfate may induce kidney tissue remodeling through direct binding and activation of the renal EGF receptor.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan;
authors.forename: Chiao-Yin
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Departments of Surgery and.
authors.forename: Guang-Huar
authors.initials: GH
authors.lastname: Young
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan;
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Hsieh
authors.affiliation: Department of Chemistry, Tamkang University, Taipei, Taiwan;
authors.forename: Yau-Hung
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Taipei Medical University Hospital, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan; and.
authors.forename: Mai-Szu
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan;
authors.forename: Jia-Hung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan leefang@adm.cgmh.org.tw.
authors.forename: Chin-Chan
authors.initials: CC
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003408:Cresols / Q000008:administration & dosage / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007200:Indican / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000601:surgery; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009392:Nephrectomy; D015398:Signal Transduction / Q000187:drug effects; D014118:Toxins, Biological / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D003408:Cresols; D014118:Toxins, Biological; C032538:4-cresol; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007200:Indican
keywords: EGF; matrix metalloproteinases; nephrotoxicity; signaling; tubule cells; uremia