The chloride intracellular channel 5A stimulates podocyte Rac1, protecting against hypertension-induced glomerular injury

Kidney Int. 2016 Apr;89(4):833-47. doi: 10.1016/j.kint.2016.01.001. Epub 2016 Feb 24.


Glomerular capillary hypertension elicits podocyte remodeling and is a risk factor for the progression of glomerular disease. Ezrin, which links podocalyxin to actin in podocytes, is activated through the chloride intracellular channel 5A (CLIC5A)-dependent phosphatidylinositol 4,5 bisphosphate (PI[4,5]P2) accumulation. Because Rac1 is involved in podocyte actin remodeling and can promote PI[4,5]P2 production we determined whether CLIC5A-dependent PI[4,5]P2 generation and ezrin activation are mediated by Rac1. In COS7 cells, CLIC5A expression stimulated Rac1 but not Cdc42 or Rho activity. CLIC5A also stimulated phosphorylation of the Rac1 effector Pak1 in COS7 cells and in cultured mouse podocytes. CLIC5A-induced PI[4,5]P2 accumulation and Pak1 and ezrin phosphorylation were all Rac1 dependent. In DOCA/Salt hypertension, phosphorylated Pak increased in podocytes of wild-type, but not CLIC5-deficient mice. In DOCA/salt hypertensive mice lacking CLIC5, glomerular capillary microaneurysms were more frequent and albuminuria was greater than in wild-type mice. Thus, augmented hypertension-induced glomerular capillary injury in mice lacking CLIC5 results from abrogation of Rac1-dependent Pak and ezrin activation, perhaps reducing the tensile strength of the podocyte actin cytoskeleton.

Keywords: albuminuria; cell signaling; chronic kidney disease; glomerulus; hyperfiltration; podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chloride Channels / metabolism*
  • Chlorocebus aethiops
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Hypertension / complications*
  • Kidney Diseases / etiology*
  • Kidney Diseases / metabolism
  • Male
  • Mice
  • Microfilament Proteins / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphorylation
  • Podocytes / metabolism*
  • Sialoglycoproteins / metabolism
  • cdc42 GTP-Binding Protein / metabolism
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / metabolism*
  • rho-Associated Kinases / metabolism


  • CLIC5 protein, human
  • Chloride Channels
  • Cytoskeletal Proteins
  • Microfilament Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Sialoglycoproteins
  • podocalyxin
  • p21-Activated Kinases
  • rho-Associated Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein