DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation
Akihito Hishikawa,
Kaori Hayashi,
Akiko Kubo,
Kazutoshi Miyashita,
Akinori Hashiguchi,
Kenichiro Kinouchi,
Norifumi Yoshimoto,
Ran Nakamichi,
Riki Akashio,
Erina Sugita,
Tatsuhiko Azegami,
Toshiaki Monkawa,
Makoto Suematsu,
Hiroshi Itoh
Affiliations
Akihito Hishikawa
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Kaori Hayashi
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Corresponding author
Akiko Kubo
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
Kazutoshi Miyashita
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Akinori Hashiguchi
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Kenichiro Kinouchi
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Norifumi Yoshimoto
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Ran Nakamichi
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Riki Akashio
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Erina Sugita
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Tatsuhiko Azegami
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Toshiaki Monkawa
Medical Education Center, Keio University School of Medicine, Tokyo, Japan
Makoto Suematsu
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
Hiroshi Itoh
Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Summary: 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.
