title: Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI.
abstract: Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair.
authors.affiliation: Division of Nephrology, Department of Medicine, Departments of Cell and Developmental Biology, and.
authors.forename: Takuto
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Skrypnyk
authors.affiliation: Departments of Developmental Biology.
authors.forename: Lauren Brilli
authors.initials: LB
authors.lastname: Skvarca
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Radostin
authors.initials: R
authors.lastname: Penchev
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Ke Xin
authors.initials: KX
authors.lastname: Zhang
authors.affiliation: Biological Sciences.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Rochon
authors.affiliation: Departments of Developmental Biology.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fall
authors.affiliation: Pathology, Vanderbilt University, Nashville, Tennessee;
authors.forename: Paisit
authors.initials: P
authors.lastname: Paueksakon
authors.affiliation: Pathology, Vanderbilt University, Nashville, Tennessee;
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Veteran Affairs Tennessee Valley Health Authority, Nashville, Tennessee; and.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Alford
authors.affiliation: Human Genetics, and.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Roman
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Raymond
authors.initials: R
authors.lastname: Harris
authors.affiliation: Departments of Developmental Biology, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hukriede
authors.affiliation: Division of Nephrology, Department of Medicine, Departments of Cell and Developmental Biology, and mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D014212:Tretinoin / Q000502:physiology*
chemical_list: D014212:Tretinoin
keywords: acute renal failure; macrophages; renal injury; renal proximal tubule cell; signaling; tubular epithelium