Treatment of renal interstitial fibrosis with an agonistic Tie2 monoclonal antibody via amelioration of peritubular capillary lesions in a mouse model of nephropathy

Abstract

Background: Chronic kidney disease (CKD) eventually manifests as renal interstitial fibrosis, and loss of peritubular capillaries in the fibrotic area is the main marker of disease progression. Tie2, as the main functional receptor of angiopoietin, is characteristically expressed in vascular endothelial cells. This study aimed to evaluate the effect and mechanism of an agonistic Tie2 monoclonal antibody on folic acid (FA)-induced renal fibrosis (FAN) in mice.Methods: Mice were randomly divided into wild-type mice, FAN model mice, and FAN model mice treated with the agonistic Tie2 antibody. Human umbilical vein endothelial cells with lipopolysaccharide-induced injury were treated with the agonistic Tie2 antibody in vitro.Results: FA-induced renal tubulointerstitial lesions could be prevented with the agonistic Tie2 antibody. The extent of renal fibrosis induced by FA was suppressed by treatment with the agonistic Tie2 antibody. The level of fibroblast-specific protein 1 was reduced in mice that were administered the agonistic Tie2 antibody. Further, the agonistic Tie2 antibody inhibited FA‐induced vascular inflammation by downregulating vascular cell adhesion molecule-1. In addition, peritubular capillary density was upregulated by agonistic Tie2 antibody treatment, as evidenced by an increase in the level of cluster of differentiation 31. These findings were verified by the in vivo results, which showed that the levels of VCAM-1, Bax, and α-smooth muscle actin were downregulated after treatment with the agonistic Tie2 antibody.Conclusions: Based on all these findings, it appears that the agonistic Tie2 antibody attenuated renal interstitial fibrosis in FAN model mice by promoting peritubular capillary regeneration, inhibiting inflammation, and improving peritubular capillary lesions, and therefore, it may have promise for the treatment of CKD.