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Mitochondrial Damage Causes Inflammation Via cGAS-STING Signaling in Acute Kidney Injury

75 Pages Posted: 8 Apr 2019 Sneak Peek Status: Under Review

See all articles by Hiroshi Maekawa

Hiroshi Maekawa

University of Tokyo - Division of Nephrology and Endocrinology; University of Tokyo - Division of CKD Pathophysiology

Tsuyoshi Inoue

University of Tokyo - Division of CKD Pathophysiology

Tzu-Ming Jao

National Taiwan University - Department of Internal Medicine

Reiko Inoue

University of Tokyo - Division of Nephrology and Endocrinology

Hiroshi Nishi

University of Tokyo - Division of Nephrology and Endocrinology

Rie Fujii

University of Tokyo - Division of Nephrology and Endocrinology; University of Tokyo - Division of CKD Pathophysiology

Fumiyoshi Ishidate

University of Tokyo - Department of Cell Biology and Anatomy

Tetsuhiro Tanaka

University of Tokyo - Division of Nephrology and Endocrinology

Yosuke Tanaka

University of Tokyo - Division of Cellular Therapy

Nobutaka Hirokawa

University of Tokyo - Department of Cell Biology and Anatomy

Masaomi Nangaku

University of Tokyo - Division of Nephrology and Endocrinology

Reiko Inagi

University of Tokyo - Division of CKD Pathophysiology

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Abstract

Mitochondrial dysfunction is central to the pathogenesis of various diseases. Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigated the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mitochondrial DNA (mtDNA) leakage into the cytosol in tubules with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which was improved in STING -deficient mice. STING knockdown in cultured tubular cells ameliorated inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies confirmed tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we concluded that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury.

Keywords: Acute kidney injury, tubular cells, Mitochondrial DNA, Inflammation, cGAS-STING pathway, Cisplatin nephrotoxicity

Suggested Citation

Maekawa, Hiroshi and Inoue, Tsuyoshi and Jao, Tzu-Ming and Inoue, Reiko and Nishi, Hiroshi and Fujii, Rie and Ishidate, Fumiyoshi and Tanaka, Tetsuhiro and Tanaka, Yosuke and Hirokawa, Nobutaka and Nangaku, Masaomi and Inagi, Reiko, Mitochondrial Damage Causes Inflammation Via cGAS-STING Signaling in Acute Kidney Injury (April 6, 2019). Available at SSRN: https://ssrn.com/abstract=3366988 or http://dx.doi.org/10.2139/ssrn.3366988
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hiroshi Maekawa

University of Tokyo - Division of Nephrology and Endocrinology

Japan

University of Tokyo - Division of CKD Pathophysiology

Japan

Tsuyoshi Inoue

University of Tokyo - Division of CKD Pathophysiology

Japan

Tzu-Ming Jao

National Taiwan University - Department of Internal Medicine

Taiwan

Reiko Inoue

University of Tokyo - Division of Nephrology and Endocrinology

Japan

Hiroshi Nishi

University of Tokyo - Division of Nephrology and Endocrinology

Japan

Rie Fujii

University of Tokyo - Division of Nephrology and Endocrinology

Japan

University of Tokyo - Division of CKD Pathophysiology

Japan

Fumiyoshi Ishidate

University of Tokyo - Department of Cell Biology and Anatomy

Japan

Tetsuhiro Tanaka

University of Tokyo - Division of Nephrology and Endocrinology

Japan

Yosuke Tanaka

University of Tokyo - Division of Cellular Therapy ( email )

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Nobutaka Hirokawa

University of Tokyo - Department of Cell Biology and Anatomy

Japan

Masaomi Nangaku

University of Tokyo - Division of Nephrology and Endocrinology

Japan

Reiko Inagi (Contact Author)

University of Tokyo - Division of CKD Pathophysiology ( email )

Japan

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