Abstract
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 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.
Highlights
Mitochondria are complex intracellular organelles with a variety of important functions, and mitochondrial homeostasis is essential for kidney function (Ishimoto and Inagi, 2016)
The present study investigated the role of mitochondrial dysfunction and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in Acute kidney injury (AKI) using a cisplatin-induced mouse model and cultured tubular cells exposed to cisplatin
We investigated the activation of the cGAS-STING pathway in the mice with ischemia-reperfusion injury (IRI), another representative AKI model (Inoue et al, 2016; Kojima et al, 2007)
Summary
Mitochondria are complex intracellular organelles with a variety of important functions, and mitochondrial homeostasis is essential for kidney function (Ishimoto and Inagi, 2016). Tubular cells have enriched mitochondria, and recent studies emphasize a pathogenic role of mitochondrial damage in the development and progression of kidney disease (Ishimoto and Inagi, 2016). Acute kidney injury (AKI) is characterized by a rapid decline in renal function; it can progress to chronic kidney disease (CKD) and is associated with high morbidity and mortality rates (Bouzas-Mosquera et al, 2009; Bucaloiu et al, 2012; Hsu, 2012; Zeng et al, 2014). To study a pathogenic role of mitochondrial damage and inflammation in AKI, we used an AKI model of a nephrotoxic reagent, cisplatin
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