Protective role of renal D-Glucuronyl C5-Epimerase (Glce) in the pathogenesis of kidney fibrosis

Abstract Fibrosis is a common pathway leading to end-stage renal failure and poses a huge threat to human health. However, the molecular mechanisms driving the fibrotic process remain poorly defined. Glucuronyl C5-epimerase (Hsepi, gene name, Glce) is a key enzyme in the biosynthesis of the heparin sulfate chains and previous studies have demonstrated homozygous Glce-/- mice show embryonic lethality and multi-organ defects. By analyzing the kidneys of patients and animal models with renal fibrosis, we observed a significant decrease in Glce protein. In addition, we found ablation of Glce exacerbated kidney fibrosis while overexpressing Glce to UUO-treated mice could improve kidney function through EGFR/ERK signaling pathway. Interestingly, the protective process did not rely on its catalytic isomerase activation. These data uncover a novel function by which Glce plays a protective role in kidney tissues, leading to reduced EMT process and renal failure in kidney fibrosis mice.