Oxidative stress in chronic renal allograft nephropathy in rats: effects of long-term treatment with carvedilol, BM 91.0228, or alpha-tocopherol.

Oxidative stress is markedly increased after kidney transplantation and may participate in the development and/or progression of chronic renal allograft nephropathy. In the present study we sought to assess the nephroprotective potential of antioxidative treatment in renal allograft recipients. Experiments were performed in the Fisher-Lewis rat model of chronic renal allograft nephropathy, with isografted Lewis rats serving as controls. Allografted rats were orally treated with carvedilol, an antihypertensive drug with antioxidative properties (25 mg/kg/d), its purely antioxidative derivative BM 91.0228 (5 mg/kg/d), alpha-tocopherol (100 mg/kg/d), a combination of propranolol/doxazosine (10/5 mg/kg/d), or vehicle for 24 weeks. At the end of the study, oxidative status and influence of antioxidative treatment were assessed in transplanted animals. Chronic allograft nephropathy was characterized by a marked increase of markers for oxidative stress (increased plasma and kidney levels of malondialdehyde, reduced glutathione, and tocopherol levels in renal allografts). Treatment with carvedilol, BM 91.0228, and tocopherol significantly improved antioxidative status of allograft kidney recipients. In addition, carvedilol reduced elevated blood pressure in allografted rats. However none of the drugs had a beneficial influence on functional and morphologic renal changes. Our data thus demonstrate that long-term treatment with the antioxidants carvedilol, BM 91.0228, or alpha-tocopherol does not prevent development of chronic transplant nephropathy, despite an improvement of antioxidative status.

Influence of acute selective endothelin-receptor-A blockade on renal hemodynamics in a rat model of chronic allograft rejection.

We have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improved survival and reduced functional and morphological kidney damage. However, the underlying mechanisms have not yet been elucidated, as ET exhibits both hemodynamic and inflammatory properties. Therefore, in the present study we investigated acute hemodynamic effects of the selective ET-A receptor antagonist LU 302146 (LU) on chronic renal allograft rejection in rats. Experiments were performed in the Fisher-to-Lewis model of chronic renal allograft rejection. Lewis-to-Lewis isografts served as controls. After 2, 12, and 24 weeks, hemodynamic measurements were performed on anesthetized animals. Measurement of mean arterial pressure (MAP) was performed via a catheter in the femoral artery. Renal blood flow (RBF) was measured by an ultrasonic flow probe placed around the renal transplant artery. Medulla blood flow (MBF) and cortex blood flow (CBF) were determined with laser Doppler probes. Hemodynamic response upon intravenous bolus injection of LU (50 mg/kg) was investigated. The application of LU was followed by a decline in MAP that reached statistical significance only in isografts (ISOs) after 12 weeks and allografts (ALLOs) after 24 weeks. RBF slightly decreased in all groups; however, without reaching statistical significance. MBF showed a small increase in ALLO12 and ALLO24 whereas CBF slightly decreased in all groups. Acute ET-A receptor blockade does not induce important hemodynamic effects in kidneys undergoing chronic rejection. The lack of response to ET-A receptor blockade suggests that the beneficial effect of ET receptor antagonists in this model is likely to be due to improvement of renal morphology.