Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes

Akihito Hishikawa; Kaori Hayashi; Takaya Abe; Mari Kaneko; Hideki Yokoi; Tatsuhiko Azegami; Mari Nakamura; Norifumi Yoshimoto; Takeshi Kanda; Yusuke Sakamaki; Hiroshi Itoh

doi:10.1016/j.celrep.2019.01.005

Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes

Cell Rep. 2019 Jan 29;26(5):1318-1332.e4. doi: 10.1016/j.celrep.2019.01.005.

Authors

Affiliations

¹ Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: kaorihayashi@keio.jp.
³ Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe, Hyogo 650-0047, Japan.
⁴ Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto 606-8507, Japan.
⁵ Department of Internal Medicine, Tokyo Dental College Hospital, 5-11-13 Sugano, Ichikawa-shi, Chiba 272-8513, Japan.

PMID: 30699357
DOI: 10.1016/j.celrep.2019.01.005

Abstract

Altered DNA methylation plays an important role in the onset and progression of kidney disease. However, little is known about how the changes arise in disease states. Here, we report that KAT5-mediated DNA damage repair is essential for the maintenance of kidney podocytes and is associated with DNA methylation status. Podocyte-specific KAT5-knockout mice develop severe albuminuria with increased DNA double-strand breaks (DSBs), increased DNA methylation of the nephrin promoter region, and decreased nephrin expression. Podocyte KAT5 expression is decreased, whereas DNA DSBs and DNA methylation are increased in diabetic nephropathy; moreover, KAT5 restoration by gene transfer attenuates albuminuria. Furthermore, KAT5 decreases DNA DSBs and DNA methylation at the same nephrin promoter region, which indicates that KAT5-mediated DNA repair may be related to DNA methylation status. These results suggest a concept in which an environment of DNA damage repair, which occurs with decreased KAT5, may affect DNA methylation status.

Keywords: DNA damage repair; DNA methylation; diabetic nephropathy; podocyte.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Albuminuria / complications
Albuminuria / pathology
Animals
Cells, Cultured
DNA Breaks, Double-Stranded
DNA Damage
DNA Methylation*
DNA Repair*
Diabetes Mellitus, Experimental / genetics
Diabetes Mellitus, Experimental / pathology
Diabetic Nephropathies / metabolism
Glomerulosclerosis, Focal Segmental / complications
Glomerulosclerosis, Focal Segmental / pathology
Glucose / toxicity
Humans
Kidney / pathology*
Kidney Glomerulus / drug effects
Kidney Glomerulus / pathology
Kidney Glomerulus / ultrastructure
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Lysine Acetyltransferase 5 / metabolism*
Membrane Proteins / metabolism
Mice, Inbred C57BL
Mice, Knockout
Podocytes / metabolism*
Promoter Regions, Genetic
Tamoxifen / pharmacology
Trans-Activators / metabolism*

Substances

Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Membrane Proteins
Trans-Activators
nephrin
Tamoxifen
KAT5 protein, human
Kat5 protein, mouse
Lysine Acetyltransferase 5
Glucose