STING Promotes the Progression of ADPKD by Regulating Mitochondrial Function, Inflammation, Fibrosis, and Apoptosis

Autosomal dominant polycystic kidney disease (ADPKD) is a predominant genetic disease, which is caused by mutations in PKD genes and is associated with DNA damage in cystic cells. The intrinsic stimulator of interferon genes (STING) pathway is crucial for recognizing damaged DNA in the cytosol, triggering the expression of inflammatory cytokines to activate defense mechanisms. However, the precise roles and mechanisms of STING in ADPKD remain elusive. In this study, we show that <i>Pkd1</i> mutant mouse kidneys show upregulation of STING, which is stimulated by the DNAs of nuclear and mitochondrial origin. The activation of STING promotes cyst growth through increasing (1) the activation of NF-κB in <i>Pkd1</i> mutant cells and (2) the recruitment of macrophages in the interstitial and peri-cystic regions in <i>Pkd1</i> mutant mouse kidneys via NF-κB mediating the upregulation of TNF-α and MCP-1. Targeting STING with its specific inhibitor C-176 delays cyst growth in an early-stage aggressive <i>Pkd1</i> conditional knockout mouse model and a milder long-lasting <i>Pkd1</i> mutant mouse model. Targeting STING normalizes mitochondrial structure and function, decreases the formation of micronuclei, induces <i>Pkd1</i> mutant renal epithelial cell death via p53 signaling, and decreases renal fibrosis in <i>Pkd1</i> mutant mouse kidneys. These results support that STING is a novel therapeutic target for ADPKD treatment.