The Effects Of Tie2 Agonist Monoantibody SH1 In Folic Acid Induced Acute Kidney Injury

Background: Acute kidney injury(AKI) is a disease with microvascular dysfunction and a newly established risk factor for the development of chronic kidney disease(CKD)and fibrosis. Recently, the endothelial Tie2 system has been recognized as endothelial protect factor through controlling vascular inflammation and permeability, which were key features of early AKI.Objectives: In this study we explored the effects of the novel Tie2 agonist SH1 in a murine model of folic acid induced acute kidney injury(FA-AKI).Methods: Part I Male CD-1 mice(4-5weeks)were injected with a single intraperitoneal dose of 250mg/kg FA dissolved in 150 mM NaHCO3.And the mice were divided into two groups: high-concentration group(24mg/ml) and low-concentration group(12mg/ml). Control animals received the same volume of NaHCO3.At 6,12,18,24 h, 2d, 3d,7d after treatment, plasma samples were collected. Plasma creatinine, blood urea nitrogen(BUN) were measured.Part II: According to result of Part I,18 h in low-concentration group was chosen to be the best time point to observe the acute phase of FA-AKI.Two hours before FA administration, SH1(1 mg/mouse in normal saline) was respectively injected via caudal vein. The mice were euthanized after 18 h of FA injection, the blood was collected from animals by retro-orbital blood collection method for the evaluation of renal function, IL-6, TNF-α,IL-10,sVCAM-1. One of the kidney was fixed in 10%formalin for histological analysis. The other kidney was stored in-80℃ for ELISA of IL-6,TNF-α, IL-10, sVCAM-1.Results: Part I The plasma BUN levels of high-concentration group increased to 13±4.37 folds by 2d and eventually decreased 7d, and the creatinine levels initially increased to approximately 6±1.17 folds by 2 days and gradually decreased in 7 days. In this group,the mortality was 38.18%. Likewise, in the low-concentration group, the level of plasma BUN were found to be elevated to about 5±2.01 folds within 18 h,while the level ofplasma creatinine increased to 3±2.29 folds in 18 h, both of which were found to decrease in 7 days, and the mortality was 0. These events suggested more severe nephrotoxicity in high concentration. Part II: The level of plasma creatinine in SH1+FA group was lower than that of FA group(p<0.05). At the same time, the IL-6,TNF-α, IL-10, sVCAM-1 level of renal homogenate and the level of IL-6,IL-10, sVCAM-1 in SH1+FA group was observed to be lower than that in FA group(p<0.05). And tubular injury in SH1+FA group was less than that in FA group, and the expression of Bcl-2/Bax in SH1+FA group was higher than that of FA group(p<0.05).Conclusions:(1)High concentration folic acid induced severe kidney injury compared with low concentration folic acid in such a AKI model.(2) SH1 can ameliorate the renal tubular epithelial injury by reducing the release of inflammatory cytokines.(3)SH1 can reduced renal tubular epithelial cell apoptosis in FA induced AKI.