title: Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-κB and p53 in proximal tubular cells.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Shimizu
authors.forename: Maimaiti
authors.initials: M
authors.lastname: Yisireyili
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Higashiyama
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Nishijima
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D015151:Immunoblotting; D007200:Indican / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D018799:Intercellular Adhesion Molecule-1; D007200:Indican