aPKCλ/ι and aPKCζ contribute to podocyte differentiation and glomerular maturation

J Am Soc Nephrol. 2013 Feb;24(2):253-67. doi: 10.1681/ASN.2012060582. Epub 2013 Jan 18.

Abstract

Precise positioning of the highly complex interdigitating podocyte foot processes is critical to form the normal glomerular filtration barrier, but the molecular programs driving this process are unknown. The protein atypical protein kinase C (aPKC)--a component of the Par complex, which localizes to tight junctions and interacts with slit diaphragm proteins--may play a role. Here, we found that the combined deletion of the aPKCλ/ι and aPKCζ isoforms in podocytes associated with incorrectly positioned centrosomes and Golgi apparatus and mislocalized molecules of the slit diaphragm. Furthermore, aPKC-deficient podocytes failed to form the normal network of foot processes, leading to defective glomerular maturation with incomplete capillary formation and mesangiolysis. Our results suggest that aPKC isoforms orchestrate the formation of the podocyte processes essential for normal glomerular development and kidney function. Defective aPKC signaling results in a dramatically simplified glomerular architecture, causing severe proteinuria and perinatal death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillaries / metabolism
  • Capillaries / pathology
  • Capillaries / ultrastructure
  • Cell Differentiation / physiology
  • Centrosome / enzymology
  • Centrosome / pathology
  • Centrosome / ultrastructure
  • Female
  • Golgi Apparatus / enzymology
  • Golgi Apparatus / pathology
  • Golgi Apparatus / ultrastructure
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / enzymology
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Podocytes / enzymology*
  • Podocytes / pathology*
  • Podocytes / ultrastructure
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Proteinuria / metabolism
  • Proteinuria / pathology
  • Proteinuria / physiopathology*
  • Signal Transduction / physiology
  • Tight Junctions / enzymology
  • Tight Junctions / pathology
  • Tight Junctions / ultrastructure

Substances

  • Isoenzymes
  • protein kinase C zeta
  • Protein Kinase C
  • protein kinase C lambda