Endothelin-1 receptor A blocker darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats

Authors

  • Ralf Bahde,

    1. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
    2. Surgical Research, Department of General and Visceral Surgery, University Hospital, Muenster, Germany
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  • Sorabh Kapoor,

    1. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
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  • Preeti Viswanathan,

    1. Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
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  • Hans-Ullrich Spiegel,

    1. Surgical Research, Department of General and Visceral Surgery, University Hospital, Muenster, Germany
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  • Sanjeev Gupta

    Corresponding author
    1. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
    2. Department of Medicine and of Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY
    • Address reprint requests to: Sanjeev Gupta, M.D., Albert Einstein College of Medicine, Ullmann Building, Room 625, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail: sanjeev.gupta@einstein.yu.edu; fax: 718-430-8975.

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  • Potential conflict of interest: Nothing to report.

  • Supported, in part, by National Institutes of Health grants R01 DK088561, R01 DK071111, and P30-DK41296. R.B. received a postdoctoral fellowship from the German Research Foundation (DFG).

Abstract

Cell transplantation-induced hepatic ischemia and recruitment of vasoconstrictors (e.g., endothelin-1; Edn1) leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan (DAR), which potently blocks Edn1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without DAR in dipeptidyl peptidase IV–deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells (KCs), neutrophils, or hepatic stellate cells (HSCs). The retrorsine-partial hepatectomy model was used for liver repopulation studies. Whether DAR was directly cytoprotective was examined in cultured rat hepatocytes or CFSC-8B rat HSCs. We found that DAR induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage, versus drug-untreated controls. Moreover, in DAR-treated animals, cell transplantation-induced activation of KCs, albeit not of neutrophils, decreased, and fewer HSCs expressed desmin. In DAR-treated rats, improvements in cell engraftment led to greater extent of liver repopulation, compared to drug-untreated controls. In cell-culture assays, DAR did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from HSCs. Moreover, DAR did not protect hepatocytes from tumor necrosis factor alpha– or oxidative stress–induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. Conclusion: Systemic administration of DAR decreases hepatic ischemia-related events and thus indirectly improves cell engraftment and liver repopulation. This vascular mechanism may permit the development of combinatorial drug-based regimens to help optimize cell therapy. (Hepatology 2014;59:1107–1117)

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