The Pathogenesis Of Proteinuria In Preeclampsia

PART 1 Expression of the Circulating,Placental and Kidney angiotensinⅡand its type 1 receptor and their Role in the Prteinuria in the Rat Model of PreeclampsiaBackground Despite recent research progress,the pathogenesis of proteinuria and kidney damage in preeclampsia is still poorly understood.Activation of kidney renin-angiotensin system(RAS) in many chronic kidney diseases has been widely accepted.It is still unknown that the relationship among circulating,palcental and kidney R.AS in the preeclampsia and their roles in the formation of proteinuria and kidney damage.Objective To investigate the expression of circulating,placental and kidney angiotensinⅡ(AngⅡ) and its type 1 receptor(AT1) in the rats with preeclampsia.Methods A rat model of preeclampsia was developed by using inhibitor of nitric oxide synthase(L-NAME).The systolic blood pressure(SBP),24hr urine protein, hepatic and renal function were compared among the virgin rat group,the normal pregnant group,nonpregnant control group and the preeclampsia group.The kidney biopsy was observed by using light and electron microscopy.ELISA and Radioimmunoassay were used to detect AngⅡin rat plasma and kidney homogenate, respectively.Placental AT1 was measured by Western blot.The level of kidney AT1 was evaluated by Immunohistochemistry and Western blot.Results In rats with preeclampsia,SBP and 24hr urine protein were increased significantly compared with control groups.There were no statistical significance of hepatic and renal function among four groups.Comparing to normal pregnancy group and virgin rat group,plasma AngⅡof preeclampsia rats was much higher(0.7058±0.130 vs 0.5398±0.055 vs 0.3663±0.123 pg/ml,P＜0.05);placental AT1 was increased 46%(0.4717±0.04981 vs 0.3199±0.03144,P＜0.05);kidney AngⅡwas decreased significantly(65.543±40.634 vs 165.543±33.078 pg/mg,P＜0.05).The expression of AT1 in kidney of preeclampsia rats was reduced evidently,which was only 54.9%of virgin group,55.0%of normal pregnancy group and 62.1%of nonpregnant control group,respectively(0.5535±0.1349 vs 1.0261±0.1402 vs 1.0073±0.1266 vs 0.8908±0.0828,P＜0.01).There was a positive correlation between 24h urinary protein excretion and the expression ofplasm AngⅡ(r=0.791,P＜0.05). Conclusions In rats model of preeclampsia,the circulating AngⅡis increased, the placental RAS is activated,while the kidney RAS is suppressed.The underlying mechanism of proteinuria and kidney damage correlation with this phenomenon in preeclampsia need further research. PART 2 The Effect of Va scular Endothel ia l Growth Factor and Its Receptors in the Proteinuria of rats with PreeclampsiaBackground Vascular endothelial growth factor(VEGF) and its receptors VEGFR(Flt-1,Flk-1) have proven to be very important facators in the formation of proteinuria in diabetes and many chronic glomerular diseases.It is widely accepted that excess placental soluble fms-like tyrosine kinase 1(sFlt-1) may contribute to endothelial dysfunction,hypertension,and proteinuria in preeclampsia.But the effect of kidney VEGF and its receptors in the formation of proteinuria in preeclampsia is still not very clear.Objective To investigate the effect of vascular endothelial growth factor (VEGF) and its receptors(VEGFR) in the proteinuria of rats with preeclampsia.Methods A rat model of preeclampsia was developed by using inhibitor of nitric oxide synthase(L-NAME).The expression of kidney VEGF and VEGFR were compared among the virgin rat group,the normal pregnant group,nonpregnant control group and the preeclampsia group.Placental VEGF was measured by Western blot.Immunohistochemistry and Western blot were used to detect the expression of kidney VEGF and VEGFR(Flt-1 and Flk-1).Results In rats with preeclampsia,the expression of placental VEGF was decreased significantly,only about 40%of that in normal pregnancy group(Western blot,1.7691±0.2707 vs 0.7155±0.2045,P＜0.05).Comparing to virgin rat group, normal pregnancy group and nonpregnant control group,kidney VEGF was enhanced evidently(Immunohistochemistry,1.5429±0.0898 vs 1.1870±0.1160 vs 1.3741±0.1165 vs 1.0155±0.0742,P＜0.01).Kidney Flt-1(Immunohistochemistry, 0.5997±0.0764 vs 0.2192±0.0113 vs 0.2105±0.0348 vs 0.3762±0.0650,P＜0.05) and Flk-1(Immunohistochemistry,0.7090±0.0421 vs 0.3999±0.0162 vs 0.4315±0.0224 vs 0.5973±0.0580,P＜0.05)were also increased significantly.Both kidney VEGF and VEGFR(Flt-1,Flk-1) had positive correlation with 24 hour urinary protein(r=0.452, 0.625,0.633,receptively,P＜0.05).Conclusions In rats model of preeclampsia,the expression of placental VEGF was decreased significantly,and kidney VEGF-VEGFR(including VEGF,Flt-1, and Flk-1) were activated.Both kidney VEGF and VEGFR(Flt-1,Flk-1) had positive correlation with 24 hour urinary protein.