Pellino1 Exacerbates Diabetic Kidney Disease Through <scp>NLRP3</scp> Inflammasome Driven Pyroptosis in Renal Tubular Epithelial Cells

Inflammatory activation is a central mechanism driving the progression of Diabetic Kidney Disease (DKD). Pyroptosis, a type of programmed cell death linked to inflammation, contributes significantly to this process. The involvement of the NLRP3 inflammasome-triggered pyroptosis pathway in DKD pathogenesis, however, requires further clarification. Pellino1, an E3 ubiquitin ligase that modulates NLRP3 inflammasome function, has been associated with multiple acute and chronic inflammatory conditions, yet its specific function in DKD is not well established. Our study revealed that Pellino1 expression is elevated in renal tissues from DKD patients and db/db mice. This increase correlated with activation of NLRP3 inflammasome-mediated pyroptosis, infiltration of macrophages into the renal interstitium, and the development of fibrosis. In vitro, high glucose (HG) stimulation enhanced the expression of both Pellino1 and key proteins involved in pyroptosis within renal tubular epithelial cells. Mechanistically, Pellino1 overexpression augmented NLRP3 inflammasome-dependent pyroptosis, an effect potentially attributable to its promotion of K63-linked ubiquitination of ASC. In contrast, either silencing Pellino1 or administering a Pellino1 inhibitor suppressed the activation of the NF-κB pathway and NLRP3-driven pyroptosis in diabetic kidneys and in HG-stimulated tubular cells. Together, these results position Pellino1 as a potential therapeutic target for alleviating inflammatory injury and fibrotic damage in DKD.