The role of LECT2 in kidney fibrosis progression and endoplasmic reticulum stress

Our previous studies showed that Leukocyte Cell-Derived Chemotaxin 2 (LECT2), as a ligand for Tie1, modulates vascular endothelial cell function, promoting hepatic fibrosis. These findings prompted an investigation into whether LECT2 effects kidney fibrosis. This study aimed to elucidate the role of LECT2 in kidney fibrosis and its regulation of C/EBP homologous protein (CHOP) expression.

We utilized Lect2-KO mice, Lect2-2 A-Cre-Rosa26-LSL-tdTomato reporter mice, and EA.hy926 cells overexpressing LECT2 to establish models of kidney fibrosis and endoplasmic reticulum stress (ERS). The expression characteristics of LECT2 in fibrotic kidneys, its effects on CHOP expression, and the mechanisms by which LECT2 modulates kidney fibrosis were systematically investigated.

Lect2 expression was upregulated in clinical fibrotic kidney samples and mouse models of fibrotic kidneys. Lect2-KO mice demonstrated reduced fibrosis and less impairment of kidney function in a kidney fibrosis model. In Lect2-KO mice, expression of the ERS marker CHOP was increased, and vascular endothelial cells were activated to express CHOP earlier, reducing kidney function damage. Overexpression of LECT2 decreased apoptosis, promoted cell survival, and upregulated the expression of profibrotic factors through activation of the EGFR/AKT/PI3K pathway. Lect2 deficiency in fibrotic kidneys led to attenuated myofibroblast activation and reduced collagen deposition.

The absence of LECT2 alleviates kidney fibrosis by inhibiting the EGFR/PI3K/AKT pathway, activating ERS, promoting partial endothelial cell apoptosis, and reducing the secretion of profibrotic factors. LECT2 emerges as a promising therapeutic target for kidney fibrosis, and its inhibition offers a potential strategy for CKD treatment.