• Hiroshi Maekawa, Tsuyoshi Inoue, Haruki Ouchi, Tzu-Ming Jao, Reiko Inoue, Hiroshi Nishi, Rie Fujii, Fumiyoshi Ishidate, Tetsuhiro Tanaka, Yosuke Tanaka, Nobutaka Hirokawa, Masaomi Nangaku, and Reiko Inagi.
• Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan; Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
• Cell Rep. 2019 Oct 29; 29 (5): 1261-1273.e6.

AbstractAcute 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 investigate 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 mtDNA leakage into the cytosol-probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane-in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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