title: Loss of Kynurenine 3-Mono-oxygenase Causes Proteinuria.
abstract: Changes in metabolite levels of the kynurenine pathway have been observed in patients with CKD, suggesting involvement of this pathway in disease pathogenesis. Our recent genetic analysis in the mouse identified the kynurenine 3-mono-oxygenase (KMO) gene (Kmo) as a candidate gene associated with albuminuria. This study investigated this association in more detail. We compared KMO abundance in the glomeruli of mice and humans under normal and diabetic conditions, observing a decrease in glomerular KMO expression with diabetes. Knockdown of kmo expression in zebrafish and genetic deletion of Kmo in mice each led to a proteinuria phenotype. We observed pronounced podocyte foot process effacement on long stretches of the filtration barrier in the zebrafish knockdown model and mild podocyte foot process effacement in the mouse model, whereas all other structures within the kidney remained unremarkable. These data establish the candidacy of KMO as a causal factor for changes in the kidney leading to proteinuria and indicate a functional role for KMO and metabolites of the tryptophan pathway in podocytes.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine; ron.korstanje@jax.org Schiffer.Mario@mh-hannover.de.|Mount Desert Island Biological Laboratory, Bar Harbor, Maine.
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.affiliation: Division of Nephrology and Hypertension, and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Deutsch
authors.affiliation: Division of Nephrology and Hypertension, and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bolanos-Palmieri
authors.affiliation: Division of Nephrology and Hypertension, and.
authors.forename: Nils
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Mount Desert Island Biological Laboratory, Bar Harbor, Maine.|Division of Nephrology and Hypertension, and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroder
authors.affiliation: Mount Desert Island Biological Laboratory, Bar Harbor, Maine.|Division of Nephrology and Hypertension, and.
authors.forename: Lynne
authors.initials: L
authors.lastname: Staggs
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany; and.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Bräsen
authors.affiliation: Department of Cellular Pathology, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom.
authors.forename: Ian S D
authors.initials: IS
authors.lastname: Roberts
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Holly
authors.initials: H
authors.lastname: Savage
authors.affiliation: Mount Desert Island Biological Laboratory, Bar Harbor, Maine.|Division of Nephrology and Hypertension, and.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Mount Desert Island Biological Laboratory, Bar Harbor, Maine; ron.korstanje@jax.org Schiffer.Mario@mh-hannover.de.|Division of Nephrology and Hypertension, and.
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D006801:Humans; D050601:Kynurenine 3-Monooxygenase / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011507:Proteinuria / Q000201:enzymology* / Q000235:genetics*; D015027:Zebrafish
chemical_list: D050601:Kynurenine 3-Monooxygenase
keywords: genetic renal disease; podocyte; proteinuria