Abstract 15399: Endothelin-1 Knockdown From Endothelial Cells Reduce Kidney Fibrosis, Peritubular Capillary Loss and Tubular Damage in Unilateral Ureteral Obstruction Model in Mice
Cardiovascular disease (CVD) is one of the complication and mortality cause of chronic kidney diseases (CKD). CKD prevention and treatment lead to both renal and cardiovascular improvements. One of the strategys to treat CKD is to prevent kidney fibrosis, that's known as a final common pathway of almost kidney diseases. Kidney fibrosis is characterized by myofibroblast formation, increasing capillary loss and renal architecture damage. Endothelin-1 (ET-1) is known as a potent vasoconstrictor substance, secreted mostly by endothelial cells and may promote fibrosis in some pathology conditions. This study's goal is to observe role of ET-1 from endothelial cells in kidney fibrosis. Unilateral ureteral obstruction (UUO) was performed to induce kidney fibrosis in vascular endothelial endothelin-1 knock out (VEETKO) and wild type (WT) mice, and sacrificed 3 and 14 days after operation. Fibrosis and myofibroblast areas were measured by sirius red staining and Alpha SMA immunohistochemical staining. Tubular damage was assessed by tubular injury score based on PAS staining. Immunofluoressence for endothelial cell (CD31) and pericyte (NG2) were done to observe peritubular capillary (PTC) number and NG2/DAPI signal area. We examined ET-1 expression by real time PCR and VEGF expression by western blot. Both VEETKO and WT underwent kidney fibrosis, but VEETKO mice had significantly lower fibrosis and myofibroblast areas. These findings were associated with higher peritubular capillary number (p<0.05) followed by reduction of pericyte expansion with lower NG2/DAPI area. ET-1 level was up-regulated both in VEETKO and WT, but VEETKO has lower expression (p<0.05). VEETKO also had significantly lower tubular injury score, suggesting reduction of tubular damage and higher VEGF expression. We showed that endothelial cells derived ET-1 knockdown could reduce both kidney fibrosis and peritubular capillary loss. These were associated with preservation of tubular architecture. Targeting ET-1 system could provide a strategy to treat kidney fibrosis, and reduce CVD mortality due to CKD.
- © 2011 by American Heart Association, Inc.