RNF130 ameliorates renal injury and inflammation by inhibiting macrophage pyroptosis through ubiquitination degradation of PDCD4 in male mice.

Abstract

Macrophage pyroptosis has been identified as a contributor to acute kidney injury (AKI), but the underlying mechanisms involved remain unclear. Herein, we identify that ring finger protein 130 (RNF130) RNF130 is significantly downregulated in both mice and patients with AKI. Myeloid cell-specific loss of RNF130 aggravates renal pathological damage and facilitates macrophage pyroptosis in AKI mouse models. Proteomics analyses and experimental validation show that RNF130 deficiency prevents the ubiquitination of programmed cell death 4 (PDCD4) dependent on the lysine 402 of PDCD4. Activated PDCD4 promotes the phosphorylation of NF-κB and STAT3, triggering NLRP3 inflammasome activation and caspase-1-mediated cleavage of GSDMD, contributing to macrophage pyroptosis. Overexpression of PDCD4 nullifies the beneficial role of RNF130. High-throughput screening of a compound library identified that Nystose effectively mitigated renal injury in ischemic AKI mice by targeting and upregulating RNF130. These findings highlight the potential of RNF130 as a promising target for AKI.

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