Global but Not Tubule Cell-Specific Knockout of STING Attenuates Kidney Injury in Mice with Unilateral Ureteral Obstruction

Background: Recent studies have identified a key role for the inflammatory mediator STING in kidney injury. Because it is activated by the cellular response to displaced DNA, it has been proposed that STING mediates kidney injury when mitochondrial DNA leaks into the cytosol of damaged tubule epithelial cells. However, STING is not specific to tubule cells, also having an important regulatory function in other cell-types, amongst them immune cells. Here, we compared the effects of deletion of STING from tubule cells with the effects of global STING deletion in mice with kidney injury caused by unilateral ureteral obstruction (UUO). Methods: Experimentswere performed in wildtype mice, Stingfl/fl mice, Pax8Cre+Stingfl/fl mice (tubule cell-specific STING knockout mice; STINGTubKO) and global STING knockout mice (STINGKO) 14 days after sham surgery or UUO. Results: mRNA and protein levels of STING were both increased >5-fold in mice after UUO. In situ hybridization and immunostaining confirmed presence of STING in damaged tubule cells, occasional glomerular cells and notably in infiltrating interstitial cells in UUO kidneys. Knockout of STING was confirmed in STINGKO mice by immunoblotting; and in STINGTubKO mice by immunohistochemistry 24h after ischemia reperfusion injury. Kidney injury was then determined by measuring mRNA levels of Havcr1, the gene encoding KIM-1, in control (Stingfl/fl) mice, STINGTubKO mice and STINGKO mice 14 days after UUO or sham surgery. Havcr1 mRNA levels were increased >120-fold in Stingfl/fl mice after UUO and they were unaffected by tubule-cell specific STING knockout. In contrast, Havcr1 mRNA levels after UUO, while increased >60-fold in global STING knockout mice, and were significantly lower than in Stingfl/fl and STINGTubKO mice after UUO (P<0.01). Conclusion: Kidney injury in UUO mice, as assessed by Havcr1 mRNA levels, is attenuated by global STING deficiency rather than tubule cell-specific STING deficiency. These findings indicate that the actions of STING in kidney disease extend beyond mediating the response to mitochondrial damage in tubule cells. The effects of STING may be primarily due to its actions in other cell-types, especially in infiltrating immune cells. Funding: Government Support – Non-U.S.