D-glucuronyl C5-epimerase binds to EGFR to suppress kidney fibrosis

Renal tubular cells may actively participate in fibrosis processes leading to end-stage renal failure. However, which molecule play pivotal role in the fibrogenesis is still vague. Glucuronyl C5-epimerase ( Hsepi , gene name, Glce ) is a key enzyme that catalyzes biosynthesis of Heparan sulfate (HS) chains attached to HS proteoglycan which are ubiquitously located on cell membrane. Homozygous Glce -/- mice may cause embryonic lethality and multi-organ defects. However, whether Glce plays a key role in kidney fibrosis is unknown. Here, we show that Glce expression is significant attenuated in kidneys of patients with renal fibrosis and the animal models. Further study shows that renal tubular-specific Glce deletion in mice exacerbate kidney fibrosis while AAV-mediated overexpressing of Glce in UUO-treated mice may ameliorate kidney fibrosis associated with epithelial-mesenchymal transition (EMT) progress via the TGF-β/Smad2/3 signaling pathway. Mechanism study demonstrates that Glce protein may bind to EGFR to inactivate EGFR/ERK signaling and further impede TGF-β/Smad-driven EMT and renal fibrosis in Glce-/- and the wild type mice. Interestingly, the anti-fibrosis function is independent of Glce enzymatic activation.

These data uncover a novel function for Glce which plays a key role in kidney tissues against fibrosis.