title: No amelioration of uromodulin maturation and trafficking defect by sodium 4-phenylbutyrate in vivo: studies in mouse models of uromodulin-associated kidney disease.
abstract: Uromodulin (UMOD)-associated kidney disease (UAKD) belongs to the hereditary progressive ER storage diseases caused by maturation defects of mutant UMOD protein. Current treatments of UAKD patients are symptomatic and cannot prevent disease progression. Two in vitro studies reported a positive effect of the chemical chaperone sodium 4-phenylbutyrate (4-PBA) on mutant UMOD maturation. Thus, 4-PBA was suggested as a potential treatment for UAKD. This study evaluated the effects of 4-PBA in two mouse models of UAKD. In contrast to previous in vitro studies, treatment with 4-PBA did not increase HSP70 expression or improve maturation and trafficking of mutant UMOD in vivo. Kidney function of UAKD mice was actually deteriorated by 4-PBA treatment. In transfected tubular epithelial cells, 4-PBA did not improve maturation but increased the expression level of both mutant and wild-type UMOD protein. Activation of NF-κB pathway in thick ascending limb of Henle's loop cells of UAKD mice was detected by increased abundance of RelB and phospho-IκB kinase α/β, an indirect activator of NF-κB. Furthermore, the abundance of NF-κB1 p105/p50, NF-κB2 p100/p52, and TRAF2 was increased in UAKD. NF-κB activation was identified as a novel disease mechanism of UAKD and might be a target for therapeutic intervention.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: kemter@lmb.uni-muenchen.de.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sklenak
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Research Center of Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Research Center of Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
authors.affiliation: Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006073:Gout / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006720:Homozygote; D033461:Hyperuricemia / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D010654:Phenylbutyrates / Q000737:chemistry*; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism; D058949:Uromodulin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D010654:Phenylbutyrates; C497594:Relb protein, mouse; D058949:Uromodulin; D051841:Transcription Factor RelB; C075773:4-phenylbutyric acid
keywords: 4-PBA; Endoplasmic Reticulum Stress; Genetic Diseases; Histone Deacetylase Inhibitors; Kidney; Molecular Chaperone; NF-κB (NF-KB); RelB; UAKD; Uromodulin (UMOD)