Confrontation with kidney inflammation through a HMGB1-targeted peptide augments anti-fibrosis therapy.

Damage to the renal tubular epithelial cells (TEC) is a key cellular event in kidney inflammation and subsequent fibrosis. However, drugs targeting renal TEC (RTEC) are limited to the alleviation of kidney fibrosis. Lethal giant larvae 1 (Lgl1) plays a key role in epithelial cell polarity and proliferation. Here, we report that the renal tubule epithelial-specific deletion of Lgl1 significantly ameliorated intrarenal inflammation and kidney fibrosis. Mechanistically, Lgl1 suppressed the activity of the deacetylase sirtuin 1 (SIRT1) and augmented the acetylation of high-mobility group box 1 (HMGB1) at the lysine 90 (K90) site. Consequently, HMGB1 migrated from the nucleus to the cytoplasm, activating an inflammatory cascade. Our renoprotective strategy was to construct a mimic peptide, TAT-K90WT, that targets HMGB1 K90 acetylation. Administration of this peptide significantly ameliorated inflammation and fibrosis in the kidneys. In summary, the Lgl1-HMGB1 axis plays an important role in renal fibrosis, and targeting HMGB1 acetylation by mimicking peptides is a potential strategy to prevent fibrosis.