D‐glucuronyl C5‐Epimerase Binds to EGFR to Suppress Kidney Fibrosis

Renal tubular cells actively participate in fibrosis, leading to end-stage renal failure. However, the key molecules involved in fibrogenesis remain unclear. Glucuronyl C5-epimerase (Hsepi, gene name, Glce) is a key enzyme that catalyzes the biosynthesis of heparan sulfate (HS) chains attached to HS proteoglycans that are ubiquitously located on the cell membrane. Homozygous Glce-/- mice may exhibit embryonic lethality and multi-organ defects. However, the role of Glce in kidney fibrosis remains unclear. This study investigated the contribution of Glce to kidney development and its role in renal fibrosis pathogenesis. Here, it shows that Glce expression is significantly attenuated in the kidneys of patients with renal fibrosis and in animal models. Renal tubular-specific Glce deletion in mice exacerbated kidney fibrosis, while AAV-mediated Glce overexpression in unilateral ureteral obstruction-treated mice ameliorated kidney fibrosis via the TGF-β/Smad2/3 signaling pathway. Mechanistic studies indicate that Glce protein may bind to epidermal growth factor receptor (EGFR) to inactivate EGFR/ERK signaling and further impede TGF-β/Smad signaling pathway and renal fibrosis in Glce-/- and wild-type mice. Notably, the anti-fibrotic function is independent of Glce enzymatic activation. These findings reveal a novel function of Glce, which plays a key role in kidney fibrosis.