title: D-Amino Acid Substitution of Peptide-Mediated NF-κB Suppression in mdx Mice Preserves Therapeutic Benefit in Skeletal Muscle, but Causes Kidney Toxicity.
abstract: In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor-κB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of κB kinase (IKK)-mediated NF-κB activation using L-isomer NF-κB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight-lysine (8K) protein transduction domain to facilitate intracellular delivery. We hypothesized that the d-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to the longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1 mg/kg) and high (10 mg/kg) doses of L- and D-isomer 8K-wild-type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild-type-NBD peptide resulted in decreased activation of NF-κB and improved histology in skeletal muscle of the mdx mouse. However, we observed kidney toxicity (characterized by proteinuria), increased serum creatinine, activation of NF-κB and pathological changes in kidney cortex that were most severe with treatment with the D-isoform of 8K-wild-type-NBD peptide. The observed toxicity was also seen in normal mice.
authors.affiliation: Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Neurology, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Reay
authors.affiliation: Department of Pathology, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Sheldon I
authors.initials: SI
authors.lastname: Bastacky
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wack
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pennsylvania, United States of America.|Center for Biologic Imaging, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Metabolism and Aging, Scripps Florida, Jupiter, Florida, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Neurology, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Paula R
authors.initials: PR
authors.lastname: Clemens
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D051550:I-kappa B Kinase