Mechanisms of the proteinuria induced by Rho GTPases

Kidney Int. 2012 Jun;81(11):1075-85. doi: 10.1038/ki.2011.472. Epub 2012 Jan 25.


Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / enzymology
  • Albuminuria / enzymology
  • Albuminuria / etiology*
  • Albuminuria / genetics
  • Albuminuria / pathology
  • Animals
  • Apoptosis
  • Gene Expression Regulation
  • Genotype
  • Glomerular Filtration Barrier / enzymology*
  • Glomerular Filtration Barrier / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Mutation
  • Phenotype
  • Podocytes / enzymology*
  • Podocytes / pathology
  • RNA, Messenger / metabolism
  • Stress Fibers / enzymology
  • Time Factors
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*


  • Membrane Proteins
  • Microfilament Proteins
  • RNA, Messenger
  • Synpo protein, mouse
  • nephrin
  • rhoA GTP-Binding Protein