title: Uromodulin retention in thick ascending limb of Henle's loop affects SCD1 in neighboring proximal tubule: renal transcriptome studies in mouse models of uromodulin-associated kidney disease.
abstract: Uromodulin-associated kidney disease (UAKD) is a hereditary progressive renal disease which can lead to renal failure and requires renal replacement therapy. UAKD belongs to the endoplasmic reticulum storage diseases due to maturation defect of mutant uromodulin and its retention in the enlarged endoplasmic reticulum in the cells of the thick ascending limb of Henle's loop (TALH). Dysfunction of TALH represents the key pathogenic mechanism of UAKD causing the clinical symptoms of this disease. However, the molecular alterations underlying UAKD are not well understood. In this study, transcriptome profiling of whole kidneys of two mouse models of UAKD, UmodA227T and UmodC93F, was performed. Genes differentially abundant in UAKD affected kidneys of both Umod mutant lines at different disease stages were identified and verified by RT-qPCR. Additionally, differential protein abundances of SCD1 and ANGPTL7 were validated by immunohistochemistry and Western blot analysis. ANGPTL7 expression was down-regulated in TALH cells of Umod mutant mice which is the site of the mutant uromodulin maturation defect. SCD1 was expressed selectively in the S3 segment of proximal tubule cells, and SCD1 abundance was increased in UAKD affected kidneys. This finding demonstrates that a cross talk between two functionally distinct tubular segments of the kidney, the TALH segment and the S3 segment of proximal tubule, exists.
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany; German Center for Vertigo and Balance Disorders, University Hospital Munich, Campus Grosshadern, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany; Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU München, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU München, Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU München, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
authors.affiliation: Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
mesh_terms: D000091307:Angiopoietin-Like Protein 7; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006073:Gout / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D033461:Hyperuricemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008138:Loop of Henle / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism; D058949:Uromodulin / Q000235:genetics* / Q000378:metabolism
chemical_list: C000599407:ANGPTL7 protein, mouse; D000091307:Angiopoietin-Like Protein 7; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C548613:Umod protein, mouse; D058949:Uromodulin; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase