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J Am Soc Nephrol. 2016 Feb;27(2):495-508. doi: 10.1681/ASN.2014111108. Epub 2015 Jun 24.

Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI.

Author information

1
Division of Nephrology, Department of Medicine, Departments of Cell and Developmental Biology, and.
2
Division of Nephrology, Department of Medicine.
3
Departments of Developmental Biology.
4
Biological Sciences.
5
Pathology, Vanderbilt University, Nashville, Tennessee;
6
Department of Pathology and Laboratory Medicine, Veteran Affairs Tennessee Valley Health Authority, Nashville, Tennessee; and.
7
Human Genetics, and.
8
Departments of Developmental Biology, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.
9
Division of Nephrology, Department of Medicine, Departments of Cell and Developmental Biology, and mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.

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.

KEYWORDS:

acute renal failure; macrophages; renal injury; renal proximal tubule cell; signaling; tubular epithelium

PMID:
26109319
PMCID:
PMC4731115
DOI:
10.1681/ASN.2014111108
[Indexed for MEDLINE]
Free PMC Article

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