cGAS Activation Accelerates the Progression of Autosomal Dominant Polycystic Kidney Disease

Background Immune cells significantly contribute to the progression of autosomal dominant polycystic kidney disease (ADPKD), the most common genetic disorder of the kidney caused by the dysregulation of the Pkd1 or Pkd2 genes. However, the mechanisms triggering the immune cells recruitment and activation are undefined. Methods Immortalized murine collecting duct cell lines were used to dissect the molecular mechanism of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activation in the context of genotoxic stress induced by Pkd1 ablation. We used conditional Pkd1 and knockout cGas-/- genetic mouse models to confirm the role of cGAS/stimulator of the interferon genes (STING) pathway activation on the course of renal cystogenesis. Results We show that Pkd1-deficient renal tubular cells express high levels of cGAS, the main cellular sensor of cytosolic nucleic acid and a potent stimulator of proinflammatory cytokines. Loss of Pkd1 directly affects cGAS expression and nuclear translocation, as well as activation of the cGAS/STING pathway, which is reversed by cGAS knockdown or functional pharmacological inhibition. These events are tightly linked to the loss of mitochondrial structure integrity and genotoxic stress caused by Pkd1 depletion because they can be reverted by the potent antioxidant mitoquinone or by the re-expression of the polycystin-1 carboxyl terminal tail. The genetic inactivation of cGAS in a rapidly progressing ADPKD mouse model significantly reduces cystogenesis and preserves normal organ functio Conclusions Our findings indicate that the activation of the cGAS/STING pathway contributes to ADPKD cystogenesis through the control of the immune response associated with the loss of Pkd1 and suggest that targeting this pathway may slow disease progression.