The Rho-GTPase Binding Protein IQGAP2 Is Required for the Glomerular Filtration Barrier

Kidney Int. 2015 Nov;88(5):1047-56. doi: 10.1038/ki.2015.197. Epub 2015 Jul 8.

Abstract

Podocyte dysfunction impairs the size selectivity of the glomerular filter, leading to proteinuria, hypoalbuminuria, and edema, clinically defined as nephrotic syndrome. Hereditary forms of nephrotic syndrome are linked to mutations in podocyte-specific genes. To identify genes contributing to podocyte dysfunction in acquired nephrotic syndrome, we studied human glomerular gene expression data sets for glomerular-enriched gene transcripts differentially regulated between pretransplant biopsy samples and biopsies from patients with nephrotic syndrome. Candidate genes were screened by in situ hybridization for expression in the zebrafish pronephros, an easy-to-use in vivo assay system to assess podocyte function. One glomerulus-enriched product was the Rho-GTPase binding protein, IQGAP2. Immunohistochemistry found a strong presence of IQGAP2 in normal human and zebrafish podocytes. In zebrafish larvae, morpholino-based knockdown of iqgap2 caused a mild foot process effacement of zebrafish podocytes and a cystic dilation of the urinary space of Bowman's capsule upon onset of urinary filtration. Moreover, the glomerulus of zebrafish morphants showed a glomerular permeability for injected high-molecular-weight dextrans, indicating an impaired size selectivity of the glomerular filter. Thus, IQGAP2 is a Rho-GTPase binding protein, highly abundant in human and zebrafish podocytes, which controls normal podocyte structure and function as evidenced in the zebrafish pronephros.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bowman Capsule / pathology
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Gene Knockdown Techniques
  • Humans
  • In Situ Hybridization
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / physiopathology*
  • Podocytes / metabolism
  • Podocytes / pathology
  • Podocytes / physiology*
  • Pronephros / growth & development*
  • Pronephros / metabolism
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism
  • ras GTPase-Activating Proteins / genetics*
  • ras GTPase-Activating Proteins / metabolism*

Substances

  • GTPase-Activating Proteins
  • IQGAP2 protein, human
  • IQGAP2 protein, zebrafish
  • Zebrafish Proteins
  • ras GTPase-Activating Proteins