The E3 ubiquitin ligase Itch plays an essential role in kidney fibrosis by inhibiting Dvl2/GSK3β/β-catenin signaling pathway.

Itch, an E3 ubiquitin ligase, is involved in various cellular functions by regulating ubiquitination and proteasomal degradation of target proteins. However, its roles are unknown in kidney fibrosis. In the present study, the decreased expression of Itch in the renal tubules of patients with chronic kidney disease (CKD) and mice induced by unilateral ureteral obstruction (UUO) or folic acid (FA) is demonstrated. Itch-/- mice exhibited more severe fibrotic lesions and inflammation after obstruction or FA treatment compared with Itch+/+ control. Itch overexpression alleviated UUO- or FA-induced kidney fibrosis and inflammation in mice. In addition, Disheveled 2 (Dvl2) deficiency reduced kidney fibrosis and inflammation in UUO mice. In vitro, Itch overexpression inhibited transforming growth factor-beta 1(TGF-β1)-induced fibrotic response in HK-2 cells. Mechanistically, Itch promoted K48-linked ubiquitination of Dvl2 at lysine 343, facilitating its proteasomal degradation, followed by suppressing GSK-3β/β-catenin signaling pathway, finally leading to the alleviation of kidney fibrosis. Collectively, our studies uncover that Itch exerts a critical role in kidney fibrosis, and it may be an attractive therapeutic target to slow the progression of fibrotic kidney disease.