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Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats

Gene Therapy volume 21, pages 484–489 (2014)Cite this article

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Abstract

Detrusor overactivity threatens the renal function of patients with spinal cord injury. Suppressing N-methyl-D-aspartate receptors is known to improve detrusor overactivity in rats with spinal cord injury, whereas kynurenic acid, the endogenous antagonist of N-methyl-D-aspartate receptors, is irreversibly synthesized by kynurenine aminotransferases (KATs). In this study, we investigated whether replication-defective herpes simplex virus vector-mediated gene transfer of human KAT II could treat detrusor overactivity by injecting the vectors into the rat bladder wall 1 week after spinal cord injury. Three weeks after injection, we evaluated the cystometry and gene expression of KAT II in L6-S1 dorsal root ganglia. The results showed that the vectors are transported to L6-S1 dorsal root ganglia and upregulate the expression of KAT II, and that they also improve the detrusor overactivity and voiding efficiency. We also proved that N-methyl-D-aspartate receptors were blocked by kynurenic acid in the extracellular solution or the vector-mediated gene transfer of KAT II in cultured rat neurons of L6-S1 dorsal root ganglia by whole-cell patch clamp to explore the mechanisms of gene therapy. Therefore, replication-defective herpes simplex virus vector-mediated KAT II inhibits detrusor overactivity in spinal cord-injured rats, possibly by suppressing N-methyl-D-aspartate receptors in bladder afferent pathways.

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Acknowledgements

This study was supported by National Natural Scientific Foundation of China (81270847, to LL) and Joint Training Foundation for Postgraduates at home and abroad of Beijing Colleges and Universities (2012, to CJ). We thank Xiulin Zhang (Department of Pharmacology and Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA) for the technical support in the patch-clamp test.

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Author notes

  1. L Liao: L Liao is a co-first author.

Authors and Affiliations

  1. Department of Urology, China Rehabilitation Research Center, Beijing, China

    C Jia & L Liao

  2. School of Rehabilitation Medicine, Capital Medical University, Beijing, China

    C Jia & L Liao

  3. Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA

    C Jia & N Yoshimura

  4. Department of Pharmacology and Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA

    N Yoshimura

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  1. C Jia
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  2. N Yoshimura
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  3. L Liao
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Correspondence to L Liao.

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Jia, C., Yoshimura, N. & Liao, L. Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats. Gene Ther 21, 484–489 (2014). https://doi.org/10.1038/gt.2014.19

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