Stimulator of Interferon Genes Is a Fine-Tuner, but Not a Prime Mover, of Kidney Inflammation

Abstract

Recent years have seen substantial scientific excitement in the role that the double-stranded DNA sensor and mediator of inflammation, stimulator of interferon genes (STING), plays in kidney disease. However, the STING pathway is not the sole regulator of inflammation, and STING has roles other than in inflammation. Here, elevated STING levels were observed in both human and mouse kidney disease, and the effects of STING deletion from kidney tubule cells, myeloid cells, and globally in experimental kidney disease were examined. Inflammatory gene up-regulation in tubule cells, induced by double-stranded DNA, was attenuated (but not negated) by STING knockout. Either myeloid or global knockout of STING marginally diminished fibroinflammatory gene up-regulation in mice with kidney injury caused by unilateral ureteral obstruction, whereas tubule cell knockout of STING unexpectedly augmented inflammatory gene up-regulation. Global knockout of STING similarly worsened diabetic kidney disease, likely due to heightened hyperglycemia. Antagonism of STING attenuated autophagy induction in human tubule cells, but not in human glomerular endothelial cells or podocytes. These findings serve as a counterweight to the enthusiasm that has recently emerged as to the roles of STING-mediated signaling in kidney disease. The actions of STING extend beyond its role in inflammation, and they are cell type dependent. STING may be a fine-tuner, but it is unlikely to be a prime mover, of inflammation in kidney disease.