TY - JOUR
T1 - DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation
AU - Hishikawa, Akihito
AU - Hayashi, Kaori
AU - Kubo, Akiko
AU - Miyashita, Kazutoshi
AU - Hashiguchi, Akinori
AU - Kinouchi, Kenichiro
AU - Yoshimoto, Norifumi
AU - Nakamichi, Ran
AU - Akashio, Riki
AU - Sugita, Erina
AU - Azegami, Tatsuhiko
AU - Monkawa, Toshiaki
AU - Suematsu, Makoto
AU - Itoh, Hiroshi
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/12/17
Y1 - 2021/12/17
N2 - The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.
AB - The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.
KW - Cell biology
KW - Pathophysiology
UR - http://www.scopus.com/inward/record.url?scp=85119902880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119902880&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103436
DO - 10.1016/j.isci.2021.103436
M3 - Article
AN - SCOPUS:85119902880
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 12
M1 - 103436
ER -