STING Promotes Renal Fibrosis in Diabetic Kidney Disease via ID1-Dependent Epithelial-Mesenchymal Transition

BACKGRUOUND: Tubulointerstitial fibrosis (TIF) due to epithelial-mesenchymal transition (EMT) is an inseparable feature of diabetic renal fibrosis. Although stimulator of interferon genes (STING) has been shown to play a potential role in regulating EMT, whether and how it modulates EMT in diabetic kidney disease (DKD) mice remain unclear. Here, we investigated the role and underlying mechanisms of STING-mediated EMT in TIF in DKD. METHODS: STING expression was detected in human renal biopsy tissues and serum samples from patients with DKD. Mouse models with genetic STING deletion or pharmacological by a STING inhibitor (C176) were established to further investigate the functions of STING in vivo. The in vitro roles of STING were analyzed in human renal tubular epithelial (HK2) cells with STING overexpression or knockdown. RNA sequencing was used to explore the underlying mechanisms. RESULTS: STING was upregulated in the kidneys and serum of patients with DKD and was negatively correlated with kidney function. STING deletion or pharmacological inhibition with C176 ameliorated pathological lesions, renal dysfunction and fibrosis in mouse models of DKD. STING deficiency alleviated renal fibrosis in DKD mice by inhibiting EMT. Mechanistically, RNA sequencing identified, inhibitor of differentiation 1 (ID1) as a downstream molecule of STING. Inhibition of ID1 in the setting of STING overexpression suppressed EMT and renal fibrosis. CONCLUSION: Our study provides evidence that STING deficiency relieves renal fibrosis by inhibiting ID1-mediated EMT and that inhibition of STING and ID1 has therapeutic potential for patients with DKD.