title: Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model.
abstract: Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yin
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Said Movahedi
authors.initials: SM
authors.lastname: Naini
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Guochun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hentschel
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; and.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; and Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts joseph_bonventre@hms.harvard.edu.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000502:physiology*; D007674:Kidney Diseases / Q000209:etiology*; D007684:Kidney Tubules; D051379:Mice; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: acute renal failure; chronic kidney disease; nephrotoxicity