title: Deletion of the Met receptor in the collecting duct decreases renal repair following ureteral obstruction.
abstract: Hepatocyte growth factor and its receptor, Met, activate biological pathways necessary for repair and regeneration following kidney injury. The Met receptor is expressed in multiple cell types within the kidney, each of which is capable of regulating fibrotic responses. To specifically address the role of the Met receptor in the adult collecting duct during renal injury, a conditional knockout mouse (Met(fl/fl);HoxB7-Cre) was generated and tested using unilateral ureteral obstruction, a model of nephron injury, fibrosis, and repair. Following obstruction in these mice there was increased expression of collagens I and IV along with plasminogen activator inhibitor 1, a known regulator of matrix degradation, compared to ureteral obstructed non-flox littermates. There were trends toward increased interstitial fibrosis, infiltration of the interstitium, and acute tubular necrosis in the knockout mice despite similar degrees of hydronephrosis to the control littermates. The Met(fl/fl);HoxB7-Cre mice; however, had reduced tubular cell proliferation and kidney regenerative capacity after release of the obstruction, thus leading to diminished functional recovery. We suggest that Met receptor signaling in the collecting duct acts as a major regulator of cell survival and propagation of the repair process with a possible secondary role to diminish inflammatory and fibrotic responses.
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Maryanna
authors.initials: M
authors.lastname: Saenko
authors.forename: Anthony
authors.initials: A
authors.lastname: Opuko
authors.forename: Akashi
authors.initials: A
authors.lastname: Togawa
authors.forename: Keita
authors.initials: K
authors.lastname: Soda
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marlier
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
authors.forename: Shuta
authors.initials: S
authors.lastname: Ishibe
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006869:Hydronephrosis / Q000378:metabolism / Q000503:physiopathology; D007685:Kidney Tubules, Collecting / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency* / Q000235:genetics; D020127:Recovery of Function; D012038:Regeneration; D013997:Time Factors; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D016326:Extracellular Matrix Proteins; D019859:Proto-Oncogene Proteins c-met