TY - JOUR
T1 - Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury
AU - Yang, Min
AU - Lopez, Lauren N.
AU - Brewer, Maya
AU - Delgado, Rachel
AU - Menshikh, Anna
AU - Clouthier, Kelly
AU - Zhu, Yuantee
AU - Vanichapol, Thitinee
AU - Yang, Haichun
AU - Harris, Raymond C.
AU - Gewin, Leslie
AU - Brooks, Craig R.
AU - Davidson, Alan J.
AU - Caestecker, Mark de
N1 - Publisher Copyright:
Copyright: © 2023, Yang et al. This is an.
PY - 2023/10
Y1 - 2023/10
N2 - Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.
AB - Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.
UR - http://www.scopus.com/inward/record.url?scp=85175006617&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.173144
DO - 10.1172/jci.insight.173144
M3 - Article
C2 - 37698919
AN - SCOPUS:85175006617
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - e173144
ER -