title: Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis.
abstract: The molecular mechanisms that maintain podocytes and consequently, the integrity of the glomerular filtration barrier are incompletely understood. Here, we show that the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (Vps34) plays a central role in modulating endocytic pathways, maintaining podocyte homeostasis. In mice, podocyte-specific conditional knockout of Vps34 led to early proteinuria, glomerular scarring, and death within 3-9 weeks of age. Vps34-deficient podocytes exhibited substantial vacuolization and foot process effacement. Although the formation of autophagosomes and autophagic flux were impaired, comparisons between podocyte-specific Vps34-deficient mice, autophagy-deficient mice, and doubly deficient mice suggested that defective autophagy was not primarily responsible for the severe phenotype caused by the loss of Vps34. In fact, Rab5-positive endosomal compartments, endocytosis, and fluid-phase uptake were severely disrupted in Vps34-deficient podocytes. Vps34 deficiency in nephrocytes, the podocyte-like cells of Drosophila melanogaster, resulted in a block between Rab5- and Rab7-positive endosomal compartments. In summary, these data identify Vps34 as a major regulator of endolysosomal pathways in podocytes and underline the fundamental roles of endocytosis and fluid-phase uptake for the maintenance of the glomerular filtration barrier.
authors.affiliation: Renal Division, University Hospital Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany.
authors.forename: Wibke
authors.initials: W
authors.lastname: Bechtel
authors.forename: Martin
authors.initials: M
authors.lastname: Helmstädter
authors.forename: Jan
authors.initials: J
authors.lastname: Balica
authors.forename: Björn
authors.initials: B
authors.lastname: Hartleben
authors.forename: Betina
authors.initials: B
authors.lastname: Kiefer
authors.forename: Fatima
authors.initials: F
authors.lastname: Hrnjic
authors.forename: Christoph
authors.initials: C
authors.lastname: Schell
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.forename: Shuya
authors.initials: S
authors.lastname: Liu
authors.forename: Felix
authors.initials: F
authors.lastname: Geist
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
mesh_terms: D000818:Animals; D001343:Autophagy; D058546:Class III Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000502:physiology*; D004331:Drosophila melanogaster; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006706:Homeostasis; D007678:Kidney Glomerulus / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000502:physiology*; D011507:Proteinuria / Q000209:etiology; D012598:Sclerosis
chemical_list: D058546:Class III Phosphatidylinositol 3-Kinases