title: Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats.
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.
authors.affiliation: 1] Department of Urology, China Rehabilitation Research Center, Beijing, China [2] School of Rehabilitation Medicine, Capital Medical University, Beijing, China [3] Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jia
authors.affiliation: 1] Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pharmacology and Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: 1] Department of Urology, China Rehabilitation Research Center, Beijing, China [2] School of Rehabilitation Medicine, Capital Medical University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Liao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D018408:Patch-Clamp Techniques; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000235:genetics*; D013119:Spinal Cord Injuries; D000637:Transaminases / Q000096:biosynthesis / Q000235:genetics*; D053201:Urinary Bladder, Overactive / Q000628:therapy*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid