Effects Of Tie2 Signal Activation On Folic Acid Induced Tubulointerstitial Lesions In Mice

BACKGROUND:Chronic kidney disease?CKD?is caused by a variety of causes of chronic abnormal renal structural and dysfunction for more than 3 months.In addition to glomerular lesions,the degree of renal tubulointerstitial lesions is closely related to prognosis of CKD.Glomerular sclerosis,renal tubular atrophy,renal interstitial inflammatory cell infiltration and fibrosis occur usually with poor prognosis.The effects of vascular injury are critical in the progression of CKD.The research of Tie2 signal pathway is currently a focus.Tie2 signal pathway could release vascular permeability,promote vascular growth and maintain vascular stability.This study is to investigate the effects of Tie2 signal activation on tubulointerstitial lesions in folic acid induced chronic kidney disease,and to provide a new target for the treatment of CKD.METHODS:Eight-week-old CD1 male mice were injected with folic acid?dissolved in 5%NaHCO₃ at a concentration of 24 mg/mL and a dose of 240 mg/kg?intraperitoneally to establish a kidney injury model,and the ratio of albumin and creatinine in urine>0.2 was thought to be successful renal injury model.The mice were injected with 5%NaHCO₃ intraperitoneally as a normal control model.The mice were divided into F+I group and F+T group.In F+I group the mice were injected with rat IgG1 antibody?1mg/mouse?intraperitoneally 24 hours after renal injury.In F+T group the mice were injected with agonist rat anti-mouse Tie2 monoclonal antibody?1mg/mouse?.The normal control group?Con group?was injected with rat IgG1 antibody?1mg/mouse?intraperitoneally.The changes of ratio of kidney and body weight were observed on the 7th and 28th day of experiment.The pathological changes of kidneys were observed by HE staining and Masson staining.The expression of CD31 was detected by immunohistochemistry.The expression of VCAM-1 was measured by Western blot.Results:?1?The kidneys of mice in Con group appeared ruddy with the normal size.On the 7^th day of experiment the kidneys of mice in F+I group were pink and swollen,and on the 28^th day of experiment the kidneys were atrophy.The kidneys of mice in F+T group had no obvious changes on the 7^th day of experiment,and the surfaces of kidneyes were slightly concave on the 28^th day.?2?The ratio of kidney and body weight increased on the7^th day in F+I group?P<0.05?,and it decreased on the 28^th day?P<0.05?.While there were no significant difference on the ratio of kidney and body weight between Con group and F+T group on the 7^th and 28^th day of experiment.?3?HE and Masson staining showed that the kidneys of mice in Con group were normal.On the 7^th day of experiment,inflammatory cells,tubule dilatation,tubular epithelial cell swelling and vacuolar degeneration could be observed in the kidneys of mice in F+I group,and on the 28^th day,the lesion was further aggravated,the tubules atrophy,a few compensatory dilatation,widened interstitial area and fibrous tissue hyperplasia could be observed.The kidney condition of mice in F+T group was relatively better.On the 7^th day and the 28^th day,the renal tubulointerstitial lesion in F+I group was more serious than that in F+T group?7d P<0.01,28d P<0.001 respectively?.?4?Immunohistochemical results showed that the microvessel density?MVD?of mice in F+I group and F+T group decreased comparing with Con group on the 7th day and the 28^th day.Compared with F+T group,MVD in F+I group also decreased?P<0.05?.?5?Western blot results showed that the expression of VCAM-1 of F+I group significantly increased compared with that of Con group?P<0.05?,while there was no significant difference on the expression of VCAM-1 between Con group and F+T group.There was no significant difference on the expression of VCAM-1 among Con group,F+I group and F+T group on the 28^th day of experiment?P>0.05?.Conclusion:?1?Tie2 signal activation can improve folic acid induced tubulointerstitial lesions in mice.?2?Tie2 signal activation may reduce the expression of vascular adhesion factor VCAM-1 and increase peritubular MVD,which can improve tubulointerstitial lesions induced by folic acid in mice.