ABSTRACT
Angiotensin II(A II) -a main effector molecule of renin-angiotensin system(RAS) has been known to increase blood pressure and glomerular capillary pressure, and filtration fraction which may be involved in the progressive renal injury process. The action of A II takes place mainly through AT1 receptor. RAS can be blocked by angiotensin converting enzyme inhibitor(ACEI) and recently developed A II AT1 receptor antagonist(AT1 RA). ACEI also activate kinin system, simultaneously. However, AT1 RA does not affect kinin system. The renoprotective mechanism of ACEI may be related with activation of kinin system. In order to evaluate the renoprotective mechanism of long-term ACEI(enalapril, 100mg/L in drinking water for 12 weeks) or AT1 RA treatment(losartan 300mg/L in drinking water for 12 weeks), and its effect on the cytokines and growth factor expressions of renal cortical tissue by compatitive RT-PCR, 46 5/6 nephrectomized(5/6 NPX) rats and 8 sham operated rats were included in this study. Five sixth NPX rats showed marked hypertensin, significant proteinuria and glomerulosclerosis(mean 30.5%) in 12 weeks after surgery. However, enelapril or losartan treated rats revealed significantly lower 24 hour urinary protein excretion(UProtV), systolic blood pressure(SBP), and glomerulosclerosis than those of control 5/6 NPX rats. Plasma renin activity and angiotensin II levels of 5/6 NPX untreated control rats were not significantly increased compared to sham operated rats in 12 week after surgery. Renal cortical renin gene expression of untreated 5/6 NPX rats was significantly suppressed compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly increased renin gene expression compared to untreated 5/6 NPX rats. Renal cortical gene expressions of TGF-beta, TNF-alpha, MCP-1, IL-6, osteopontin, and endothelin-1 were significantly increased in 5/6 NPX untreated control rats compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly less level of renal TGF-beta gene expression compared to 5/6 NPX control rats. The magnitude of SBP and UProtV were significantly positively correlated with the degree of glomeruloslerosis(p<0.001, p<0.001). With the above result, we speculate that because ACEI or AT1 RA showed similar renoprotective effect in 5/6 NPX rats, at least in part, local activation of RAS plays an important role in the progressive renal injury process of this model.
Subject(s)
Animals , Rats , Angiotensin Amide , Angiotensin II , Angiotensins , Blood Pressure , Capillaries , Cytokines , Drinking Water , Enalapril , Endothelin-1 , Filtration , Gene Expression , Interleukin-6 , Losartan , Osteopontin , Peptidyl-Dipeptidase A , Plasma , Proteinuria , Renin , Renin-Angiotensin System , Transforming Growth Factor beta , Tumor Necrosis Factor-alphaABSTRACT
Angiotensin II(A II) -a main effector molecule of renin-angiotensin system(RAS) has been known to increase blood pressure and glomerular capillary pressure, and filtration fraction which may be involved in the progressive renal injury process. The action of A II takes place mainly through AT1 receptor. RAS can be blocked by angiotensin converting enzyme inhibitor(ACEI) and recently developed A II AT1 receptor antagonist(AT1 RA). ACEI also activate kinin system, simultaneously. However, AT1 RA does not affect kinin system. The renoprotective mechanism of ACEI may be related with activation of kinin system. In order to evaluate the renoprotective mechanism of long-term ACEI(enalapril, 100mg/L in drinking water for 12 weeks) or AT1 RA treatment(losartan 300mg/L in drinking water for 12 weeks), and its effect on the cytokines and growth factor expressions of renal cortical tissue by compatitive RT-PCR, 46 5/6 nephrectomized(5/6 NPX) rats and 8 sham operated rats were included in this study. Five sixth NPX rats showed marked hypertensin, significant proteinuria and glomerulosclerosis(mean 30.5%) in 12 weeks after surgery. However, enelapril or losartan treated rats revealed significantly lower 24 hour urinary protein excretion(UProtV), systolic blood pressure(SBP), and glomerulosclerosis than those of control 5/6 NPX rats. Plasma renin activity and angiotensin II levels of 5/6 NPX untreated control rats were not significantly increased compared to sham operated rats in 12 week after surgery. Renal cortical renin gene expression of untreated 5/6 NPX rats was significantly suppressed compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly increased renin gene expression compared to untreated 5/6 NPX rats. Renal cortical gene expressions of TGF-beta, TNF-alpha, MCP-1, IL-6, osteopontin, and endothelin-1 were significantly increased in 5/6 NPX untreated control rats compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly less level of renal TGF-beta gene expression compared to 5/6 NPX control rats. The magnitude of SBP and UProtV were significantly positively correlated with the degree of glomeruloslerosis(p<0.001, p<0.001). With the above result, we speculate that because ACEI or AT1 RA showed similar renoprotective effect in 5/6 NPX rats, at least in part, local activation of RAS plays an important role in the progressive renal injury process of this model.
Subject(s)
Animals , Rats , Angiotensin Amide , Angiotensin II , Angiotensins , Blood Pressure , Capillaries , Cytokines , Drinking Water , Enalapril , Endothelin-1 , Filtration , Gene Expression , Interleukin-6 , Losartan , Osteopontin , Peptidyl-Dipeptidase A , Plasma , Proteinuria , Renin , Renin-Angiotensin System , Transforming Growth Factor beta , Tumor Necrosis Factor-alphaABSTRACT
In order to evaluate the renal expression of renin, TGF-beta, TNF-alpha, IL-6, MCP-1, endothelin-1, osteopontin, and the role of renin-angiotensin system(RAS) in renal injury mechanism of experimental unilateral ureteral obstruction(UUO), 44 male Sprague-Dawley rats weighing 260-280g underwent sham operation(n= 8), UUO without treatment(n=12), UUO with angiotensin converting enzyme inhibitor(ACEI, enalapril 100 mg/kg body weight in drinking water, n=12) and UUO with angiotensin II AT1 receptor antagonist(AT1 RA, losartan 300mg/Kg body weight in drinking water, n= 12) under thiopental sodium anesthesia(50mg/kg, body weight, I.P.). Half number of each group was sacrificed at 3 and 7 days after surgery. With standard point count method, we evaluated the magnitude of tubulointerstitial mononuclear cell infiltration and relative volume of interstitium by light microscopic examination (PAS stain and immunohistochemistry for ED-1). Competitive RT-PCR was performed for the estimation of renin, TGF-beta, TNF-alpha, IL-6, MCP-1, endothelin-1, osteopontin and beta-actin gene expression levels of the kidneys. Renal gene expressions of renin, TGF-beta, MCP-1, TNF-alpha, IL-6, endothelin-1, and osteopontin of untreated control UUO rats were significantly increased compared to sham operated rats at 3 and 7 days after surgery. The level of TGF-beta, TNF-alpha, IL-6 and endothelin-1 gene expressions of ACEI treated UUO rats was significantly lower than those of untreated control UUO rats. AT1 RA treated UUO rats also showed significantly lower level of TGF-beta and osteopontin gene expression than those of control UUO group. Untreated control UUO rats showed significantly increased mononuclear cell infiltration of tubulointerstitium and relative volume of interstitium of the kidney compared to sham operated rats. ACEI or AT1 RA treated UUO rats showed significantly less relative volume of interstitium and mononuclear cell infiltration than those of untreated UUO rats(p<0.05, p<0.05). With the above result, we speculate that the upregulation of renin, TGF-beta, MCP-1, TNF-alpha, IL-6, osteopontin and endothelin-1 genes is closely related to the progressive renal injury process in this model and at least in part, the early activation of renin angiotensin system of the kidney is involved in this mechanism.