title: Inhibition of MTOR disrupts autophagic flux in podocytes.
abstract: Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada.
authors.forename: Davide P
authors.initials: DP
authors.lastname: Cinà
authors.forename: Tuncer
authors.initials: T
authors.lastname: Onay
authors.forename: Aarti
authors.initials: A
authors.lastname: Paltoo
authors.forename: Chengjin
authors.initials: C
authors.lastname: Li
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maezawa
authors.forename: Javier
authors.initials: J
authors.lastname: De Arteaga
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008247:Lysosomes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus