DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages.

Erina Sugita Nishimura, Akihito Hishikawa, Ran Nakamichi, Riki Akashio, Shunsuke Chikuma, Akinori Hashiguchi, Norifumi Yoshimoto, Eriko Yoshida Hama, Tomomi Maruki, Wataru Itoh, Shintaro Yamaguchi, Jun Yoshino, Hiroshi Itoh, Kaori Hayashi

Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. · pubmed

Paper

Abstract

DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6C

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Research summary

DNA damage in renal proximal tubular epithelial cells leads to systemic metabolic dysfunction through altered macrophage activity. The study addresses the role of DNA damage in aging-related kidney dysfunction and its systemic effects, which is pertinent to understanding the mechanisms of aging and potential interventions.

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