Studies On The Function Of Endothelin-1 And Angiotensin II In Rat Model Of Chronic Nephrotoxicity Of Cyclosporine A

Objective To explore the effects of endothelin-1 and angiotensin Ⅱ on chronic nephrotoxicity of cyclosprine A and the interact of each other in rat model.Methods The Wistar rats were fed on salt depletion diet for 7 days and then randomly divided into 4 groups : control group (Group A, n = 6) , CsA 10mg/(kg·d) (Group B, n = 6) , CsA 15mg/(kg·d) (Group C, n =6) , CsA 20mg/(kg·d) ( Group D, n= 6) . The rats were injected subcutaneously for 4 weeks consecutively to develop chronic nephrotoxicity of cyclosprine A. Two days before CsA was injected , furosemide was administered by intraperitoneal injection of 8mg/kg and salt depletion diet lasted the whole experiment so that salt depletion model appears. Four weeks later , the rats were sacrificed, blood and kidneys were taken out. Radioimmunoassay was used to study the changes of endothelin-1 and angiotensin Ⅱ in plasma, cortex and medulla. We utilized immunohistochemistry in observation of the distribution and content of endothelin-1 and angiotensin Ⅱ in kidney cortex and medulla. Results Plasma endothelin-1 in CsA-given group has no significant difference with control group. Endothelin-1 in both cortex and medulla significantly increased in contrast to control group, except medulla inGroup D. Angiotensin II of plasma,cortex and medulla in CsA-given group increased significantly compared with control group.The increase was related to CsA concentration, except Group D. The expression of endothelin-1 and angiotensin II elevated in CsA-given group on immunohistochemistry slices, most of particles are distributed in renal tubular epithelial cells , especially in distal tubular. With the increase of drug, ET-1 content in glomerulus increased. Endothelium and mesangial cell express endothelin-1 and angiotensin II.Conclusion: There is no significant evidence that serum creatine is attached to CsA concentration so chronic nephrotoxicity of cyclosprine A can' t be measured by CsA concentration only. Endothelin-1 is an important cause of renal tubular fibrosis and necrosis in chronic nephrotoxicity of cyclosprine A. in higher dose, Endothelin-1 involves in glomerulus lesion. Endothelin-1 rised with the elevating of angiotensin II There is probably relationship between endothelin-1 andangiotensin II.