Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-κB and p53 in proximal tubular cells

Life Sci. 2013 Feb 7;92(2):143-8. doi: 10.1016/j.lfs.2012.11.012. Epub 2012 Nov 28.

Abstract

Aims: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in adhesion of monocytes/macrophages to injured tubulointerstitial tissue. The present study aimed to determine if indoxyl sulfate, a uremic toxin, regulates renal expression of ICAM-1.

Main methods: The effect of indoxyl sulfate on expression of ICAM-1 was determined using human proximal tubular cells (HK-2 cells) and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS).

Key findings: DN+IS, DH, and DH+IS rats showed significantly increased mRNA expression of ICAM-1 in the kidneys compared with DN rats. DH+IS rats showed significantly increased mRNA expression of ICAM-1 in the kidneys compared with DH rats. Immunohistochemistry revealed that ICAM-1 was localized in the cytoplasm of renal tubular cells, and was most prominently expressed in DH+IS rats. Indoxyl sulfate upregulated mRNA and protein expression of ICAM-1 in HK-2 cells. Inhibitors of NADPH oxidase (diphenylene iodonium chloride), NF-κB (isohelenin) and p53 (pifithrin-α,p-nitro) suppressed indoxyl sulfate-induced expression of ICAM-1 mRNA and protein in HK-2 cells.

Significance: Indoxyl sulfate upregulated renal expression of ICAM-1 through production of reactive oxygen species (ROS) such as superoxide, and activation of NF-κB and p53 in proximal tubular cells. Further, administration of indoxyl sulfate promoted ICAM-1 expression in rat kidneys. Thus, accumulation of indoxyl sulfate in chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of ICAM-1 in the kidney.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Immunoblotting
  • Indican / pharmacology*
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / physiology
  • Kidney Cortex / drug effects
  • Kidney Cortex / metabolism
  • Kidney Cortex / physiology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / physiology
  • NF-kappa B / biosynthesis*
  • NF-kappa B / physiology
  • Rats
  • Rats, Inbred Dahl
  • Real-Time Polymerase Chain Reaction
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Protein p53 / physiology
  • Up-Regulation / drug effects

Substances

  • NF-kappa B
  • Tumor Suppressor Protein p53
  • Intercellular Adhesion Molecule-1
  • Indican