Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

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.

Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

“…The tumour uptake expressed as the area under the normalised uptake value curve (AUC) was higher with the gefitinib treatment but decreased with the cys A treatment ( Figure 6 B). We attributed the effects to the broad ATP-binding-cassette (ABC) transporter substrate and enhanced the drug delivery activity of gefitinib [ 44 , 45 ] and the vasoconstrictive nature of cys A in vivo [ 46 , 47 ], in addition to its ABCB4 inhibitory activity. In view of these findings, we also expressed the data as the fractional retention of uptake at 60 min relative to 3.5 min (FRT) ( Figure 6 C).…”

Evaluation of renoprotective effect of grape seed proanthocyanidin extract on Cyclosporine A- induced Nephrotoxicity by mitigating inflammatory response, oxidative stress and apoptosis in rats

“…Apoptosis increased oxidative stress, and mitochondrial dysfunction were reported in CsA nephrotoxicity (Hausenloy et al, 2012). Renal failure was the end stage resulted from nephrotoxicity associated with long term administration of Cyclosporine A (Caires et al, 2018). Cyclosporine A treated rats revealed a significant increase in serum concentration of urea and creatinine.…”

Thymoquinone suppressed Cyclosporine A- induced Nephrotoxicity in rats via antioxidant activation and inhibition of inflammatory and apoptotic signaling pathway

“…Apoptosis increased oxidative stress, and mitochondrial dysfunction were reported in CsA nephrotoxicity (Hausenloy et al, 2012). Renal failure was the end stage results from nephrotoxicity associated with long term administration of Cyclosporine A (Caires et al, 2018).…”