{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:14:17Z","timestamp":1792080857054,"version":"4.4.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,7]]},"abstract":"\n 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\n \u03ba<\/jats:italic>\n LCs (RFS-\n \u03ba<\/jats:italic>\n LCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human\n \u03ba<\/jats:italic>\n LCs (25\n \u03bc<\/jats:italic>\n g\/ml). Before the onset of renal failure, mice overexpressing RFS-\n \u03ba<\/jats:italic>\n LCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of\n \u03ba<\/jats:italic>\n LCs. Exposure of PT cells to RFS-\n \u03ba<\/jats:italic>\n LCs resulted in\n \u03ba<\/jats:italic>\n LC 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-\n \u03ba<\/jats:italic>\n LC variable (V) sequence, because they did not occur with control LCs or the same RFS-\n \u03ba<\/jats:italic>\n LC carrying a single substitution (Ala30\u2192Ser) in the V domain. The lysosomal alterations induced by RFS-\n \u03ba<\/jats:italic>\n LCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific\n \u03ba<\/jats:italic>\n LCs 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.\n <\/jats:p>","DOI":"10.1681\/asn.2015050581","type":"journal-article","created":{"date-parts":[[2015,11,27]],"date-time":"2015-11-27T22:08:33Z","timestamp":1448662113000},"page":"2049-2061","source":"Crossref","is-referenced-by-count":69,"title":["Impaired Lysosomal Function Underlies Monoclonal Light Chain\u2013Associated Renal Fanconi Syndrome"],"prefix":"10.1681","volume":"27","author":[{"given":"Alessandro","family":"Luciani","sequence":"first","affiliation":[{"name":"Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Sirac","sequence":"additional","affiliation":[{"name":"Department of Immunology, National Center for 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for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Bender","sequence":"additional","affiliation":[{"name":"Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France;"},{"name":"Department of Nephrology, University Hospital, Poitiers University, Poitiers, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Bonaud","sequence":"additional","affiliation":[{"name":"Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Cogn\u00e9","sequence":"additional","affiliation":[{"name":"Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Aucouturier","sequence":"additional","affiliation":[{"name":"Department of Immunology, National Institute of Health and Medical Research Unit 938, Saint Antoine Hospital, Pierre et Marie Curie University, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Ronco","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Dialysis, Tenon Hospital, Paris, France;"},{"name":"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;"},{"name":"Sorbonne Universit\u00e9s, UPMC University of Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Bridoux","sequence":"additional","affiliation":[{"name":"Department of Immunology, National 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