title: Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress-Related Kidney Diseases.
abstract: Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin β2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.
authors.affiliation: Division of Nephrology, Department of Internal Medicine.
authors.forename: Yeawon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine.
authors.forename: Heedoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Division of Urology, Department of Surgery.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manson
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.affiliation: Proteomics and Mass Spectrometry Facility, Donald Danforth Plant Science Center, St. Louis, Missouri.
authors.forename: Bradley
authors.initials: B
authors.lastname: Evans
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Departments of Cell Biology and Physiology and.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; Pathology and Immunology, and.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.affiliation: Division of Nephrology, Department of Internal Medicine, ychen@dom.wustl.edu.
authors.forename: Ying Maggie
authors.initials: YM
authors.lastname: Chen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine; D059865:Endoplasmic Reticulum Stress; D007674:Kidney Diseases / Q000209:etiology / Q000652:urine*; D051379:Mice; D009414:Nerve Growth Factors / Q000652:urine*
chemical_list: D015415:Biomarkers; C534671:MANF protein, mouse; D009414:Nerve Growth Factors
keywords: acute renal failure; endoplasmic reticulum; nephrotic syndrome