Abstract
Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.
Highlights
Cyclosporine-A (CsA) is an agent widely used in transplants, such as kidney transplant [1]
Treatment with CsA showed a tendency to decrease weight, there was no significant difference in the weight of the CsA, CsA and bosentan group (CsA+BOS) and CsA and macitentan group (CsA+MAC) groups compared to the control group (Figure 1A)
Renal lesions were observed in rats in subacute toxicity. This was associated with an increased serum creatinine and a decrease in glomerular filtration rate, arteriolar lesions and arterial hypertension
Summary
Cyclosporine-A (CsA) is an agent widely used in transplants, such as kidney transplant [1] It is a cyclic, lipophilic medicine, and has immunosuppressive activity to T cells and other inflammatory cells. Lipophilic medicine, and has immunosuppressive activity to T cells and other inflammatory cells It binds to cyclophilin, its cytoplasmic receptor, and the CsA-cyclophilin complex binds to calcineurin, a serine-threonine phosphatase that is calcium- and calmodulin-dependent, inhibiting their ability to dephosphorylate nuclear factors present in the cytosol [2,3] as nuclear factor T cells (NF-ATc). CsA blocks NF-ATc and inhibits the transcription process, preventing the production of these cytokines [4]. The adverse effects, such as nephrotoxicity, hepatotoxicity, hypertension and risk of malignancy, are observed in sub-acute and chronic treatment [5]. The tubular atrophy and irreversible interstitial fibrosis, initially compromising the medullary rays and after the renal cortex, are observed [6]
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