Ring-finger protein 5 protects against diabetic kidney disease by targeting and degrading STING

The stimulator of interferon genes (STING) has been recognized as a pivotal modulator in the pathological progression of diabetic kidney disease (DKD). Ring-finger protein 5 (RNF5) is an important modulator of STING and is implicated in various disease processes. Nevertheless, the function of RNF5/STING axis in the context of DKD has yet to be investigated. This research was undertaken to explore whether RNF5 regulates the progression of DKD through modulation of the STING pathway, as well as to clarify the mechanisms involved. We found that RNF5 levels were significantly reduced in high glucose (HG)-stimulated HK-2 cells and the kidneys of diabetic mice. Upregulation of RNF5 inhibited HG-induced cellular injury, fibrosis, and inflammatory responses, while RNF5 knockdown exacerbated these detrimental effects. Moreover, HG treatment led to increased levels of STING, phosphorylated TBK1, phosphorylated IRF-3, and phosphorylated NF-κB, indicating STING pathway activation. RNF5 overexpression significantly suppressed the activation of the STING pathway induced by HG, whereas RNF5 knockdown enhanced it. Mechanistically, RNF5 promoted the ubiquitination and degradation of STING. Inhibition of STING abolished the exacerbating effect of RNF5 knockdown on HG-induced cellular injury. Animal studies revealed that RNF5 overexpression alleviated kidney damage, fibrosis, and inflammation in diabetic mouse models, concomitantly suppressing STING pathway activation. Collectively, RNF5 inhibits HG-induced tubular cell injury by promoting STING degradation, thereby suppressing STING pathway activation. Targeting RNF5 could be a potentially effective therapeutic approach for DKD.