RESUMEN
OBJECTIVE: To investigate the therapeutic effects of endothelin receptor antagonist (bosentan) and angiotensin II type 1 receptor antagonist (valsartan) on renal interstitial fibrosis of rats with chronic aristolochic acid nephropathy (CAAN). METHODS: A rat model of CAAN was established by gavage with extract of Aristolochia manshuriensis Kom intermittently, and then they were divided into the following three groups, i.e. model group, bosentan group (100 mg.kg(-1).d(-1) by gavage) and valsartan group (30 mg .kg(-1).d(-1) by gavage). Control group (CTR) only received tap water by gavage. Each group consisted of 6 rats. At the end of 1st, 4 th, 8 th, 12 th and 16 th week, urinary protein excretion, urinary beta2 microglobulin (beta2-mG) and serum creatinine (SCr) were measured. Afterwards the rats were sacrificed. The relative area of renal interstitial fibrosis on pathological section was semi-quantitatively determined. The mRNA and the protein expression of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen I (ColI) in kidney tissue was semi-quantitatively determined with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. RESULTS: Compared with CTR, urinary protein excretion, urinary beta2-mG and Scr were significantly increased (P < 0.05 or 0.01) and relative area of interstitial fibrosis was also significantly enlarged in the model group (3.964 +/- 0.739%, CTR 0.158 +/- 0.059%, P < 0.01). Compared with CTR, the expression of TGF-beta1, CTGF, PAI-1, TIMP-1 and Col I mRNA and protein was significantly up-regulated in the model group (P < 0.01). After intervention with bosentan or valsartan the up-regulating above mentioned parameters were all significantly inhibited (P < 0.05 or 0.01). However, there was no difference between bosentan group and valsartan group. CONCLUSION: Bosentan and valsartan both can ameliorate renal interstitial fibrosis and improve renal function in rats with CAAN. These responses may result from the inhibition effects on the promoting factors of ECM synthesis (TGF-beta1, CTGF) and the antagonistic factors of ECM degradation (PAI-1, TIMP-1).
Asunto(s)
Enfermedades Renales/tratamiento farmacológico , Riñón/patología , Sulfonamidas/farmacología , Tetrazoles/farmacología , Valina/análogos & derivados , Animales , Ácidos Aristolóquicos/toxicidad , Bosentán , Colágeno Tipo I/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas , Ratas Sprague-Dawley , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Valina/farmacología , ValsartánRESUMEN
OBJECTIVE: To investigate the interrelation between endothelin-1 (ET-1) and angiotensin II (AngII) in kidney tissue of rats with diabetic nephropathy. METHODS: Wistar rats were performed a removal operation of right kidney. Two weeks later the uninephrectomized rats were given intravenous injection of streptozotocin (STZ, 35 mg/kg). The diabetic rats were randomly divided into the following four groups: DM + bos group (bosentan 100 mg/kg/d by gavage); DM + ena group (enalapril 10 mg/kg/d by gavage); DM + bos + ena group (the same doses of both bosentan and enalapril by gavage); DM + veh group (only buffer by gavage). Besides, uninephrectomized rats without STZ injection were assigned as control group. Each group consisted of 6 rats. Twenty weeks later, they were sacrificed and left kidney of each rat was harvested respectively. The mRNA expression of angiotensinogen (Ao), angiotensin type 1 receptor (AT1R), preproendothelin-1 and endothelin A receptor (ETaR), and the protein expression of AngII, AT1R, ET-1 and ETaR in kidney tissue were semi-quantitatively detected with reverse transcription- polymerase chain reaction and immunohistochemical staining respectively. RESULTS: In the diabetic group without treatment (DM + veh group), the expression of Ao (AII), AT1R and ET-AR was significantly up-regulated (1.25, 1.94 and 2.56-folds in mRNA respectively, 2.52, 3.84 and 3.30-folds in protein respectively, P < 0.01 or P < 0.05) compared with control group. In three treatment groups, i.e. DM + bos group, DM + ena group and DM + bos + ena group, the up-regulated expression of Ao (AII), AT1R and ET-AR was significantly attenuated (-38.2% to -54.8% in mRNA and -55.3% to -69.7% in protein, P < 0.05 or P < 0.01) compared with DM group. The inhibitory rates among these three treatment groups had no significant difference (P > 0.05). In this study, the expression of preproendothelin-1 mRNA and ET-1 protein was not significantly changed among all groups (P > 0.05). CONCLUSION: Either endothelin receptor antagonist or ACE inhibitor can significantly inhibit the expression of AngII, AT1R and ETaR in kidney tissue of diabetic rats, which suggest that there are close relationship and cross action between ET-1 and AngII.