Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis

J Am Soc Nephrol. 2013 Apr;24(5):727-43. doi: 10.1681/ASN.2012070700. Epub 2013 Mar 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Class III Phosphatidylinositol 3-Kinases / deficiency
  • Class III Phosphatidylinositol 3-Kinases / physiology*
  • Drosophila melanogaster
  • Endocytosis*
  • Endosomes / metabolism
  • Homeostasis*
  • Kidney Glomerulus / pathology
  • Mice
  • Mice, Inbred C57BL
  • Podocytes / physiology*
  • Proteinuria / etiology
  • Sclerosis


  • Class III Phosphatidylinositol 3-Kinases