Mechanisms of angiotensin II signaling on cytoskeleton of podocytes

J Mol Med (Berl). 2008 Dec;86(12):1379-94. doi: 10.1007/s00109-008-0399-y. Epub 2008 Sep 5.

Abstract

Podocytes are significant in establishing the glomerular filtration barrier. Sustained rennin-angiotensin system (RAS) activation is crucial in the pathogenesis of podocyte injury and causes proteinuria. This study demonstrates that angiotensin II (Ang II) caused a reactive oxygen species (ROS)-dependent rearrangement of cortical F-actin and a migratory phenotype switch in cultured mouse podocytes with stable Ang II type 1 receptor (AT1R) expression. Activated small GTPase Rac-1 and phosphorylated ezrin/radixin/moesin (ERM) proteins provoked Ang II-induced F-actin cytoskeletal remodeling. This work also shows increased expression of Rac-1 and phosphorylated ERM proteins in cultured podocytes, and in glomeruli of podocyte-specific AT1R transgenic rats (Neph-hAT1 TGRs). The free radical scavenger DMTU eliminated Ang II-induced cell migration, ERM protein phosphorylation and cortical F-actin remodeling, indicating that ROS mediates the influence of Rac-1 on podocyte AT1R signaling. Heparin, a potent G-coupled protein kinase 2 inhibitor, was found to abolish ERM protein phosphorylation and cortical F-actin ring formation in Ang II-treated podocytes, indicating that phosphorylated ERM proteins are the cytoskeletal effector in AT1R signaling. Moreover, Ang II stimulation triggered down-regulation of alpha actinin-4 and reduced focal adhesion expression in podocytes. Signaling inhibitor assay of Ang II-treated podocytes reveals that Rac-1, RhoA, and F-actin reorganization were involved in expressional regulation of alpha actinin-4 in AT1R signaling. With persistent RAS activation, the Ang II-induced phenotype shifts from being dynamically stable to adaptively migratory, which may eventually exhaust podocytes with a high actin cytoskeletal turnover, causing podocyte depletion and focal segmental glomerulosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Actins / ultrastructure
  • Angiotensin II / metabolism*
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Shape
  • Cytoskeleton / metabolism*
  • Cytoskeleton / ultrastructure
  • Gene Expression Regulation
  • Humans
  • Mice
  • Podocytes / cytology*
  • Podocytes / metabolism*
  • Podocytes / ultrastructure
  • Rats
  • Rats, Transgenic
  • Reactive Oxygen Species / metabolism
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism

Substances

  • Actins
  • Reactive Oxygen Species
  • Receptor, Angiotensin, Type 1
  • Angiotensin II