title: Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome.
abstract: Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Luciani
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France; National Reference Center for Amyloidosis and other Monoclonal Immunoglobulin Deposition Diseases, University Hospital of Limoges, Poitiers, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Sirac
authors.affiliation: Division of Nephrology, UCL Medical School, Brussels, Belgium;
authors.forename: Sara
authors.initials: S
authors.lastname: Terryn
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France; Department of Nephrology, University Hospital, Poitiers University, Poitiers, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Javaugue
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
authors.forename: Jenny Ann
authors.initials: JA
authors.lastname: Prange
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France; Department of Nephrology, University Hospital, Poitiers University, Poitiers, France;
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bender
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France;
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonaud
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.affiliation: Department of Immunology, National Institute of Health and Medical Research Unit 938, Saint Antoine Hospital, Pierre et Marie Curie University, Paris, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Aucouturier
authors.affiliation: Department of Nephrology and Dialysis, Tenon Hospital, Paris, France; Department of Immunology, National Institute of Health and Medical Research Unit 938, Saint Antoine Hospital, Pierre et Marie Curie University, Department of Nephrology and Dialysis, Tenon Hospital, Paris, France; Sorbonne Universités, UPMC University of Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.affiliation: Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France; Department of Nephrology, University Hospital, Poitiers University, Poitiers, France; f.bridoux@chu-poitiers.fr olivier.devuyst@uzh.ch.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Division of Nephrology, UCL Medical School, Brussels, Belgium; f.bridoux@chu-poitiers.fr olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000818:Animals; D005198:Fanconi Syndrome / Q000209:etiology*; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010265:Paraproteinemias / Q000150:complications*
chemical_list: D007147:Immunoglobulin Light Chains
keywords: cell & transport physiology; endocytosis; multiple myeloma; proximal tubule; renal proximal tubule cell