Indoxyl sulfate upregulates renal expression of icam-1 via production of ros and activation of nf-κb and p53 in proximal tubular cells

Abstract

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in adhesion of monocytes/macrophages to injured tubulointerstitial tissue. The present study examined whether indoxyl sulfate, a uremic toxin, regulates renal expression of ICAM-1. The effect of indoxyl sulfate on expression of ICAM-1 was determined using human proximal tubular cells (HK-2 cells) and 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). 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. Indoxyl sulfate upregulated mRNA expression of ICAM-1 in HK-2 cells. Inhibitors of NADPH oxidase, NF-κB and p53 suppressed indoxyl sulfate-induced mRNA expression of ICAM-1 in HK-2 cells. In conclusion, indoxyl sulfate upregulates renal expression of ICAM-1 through production of ROS and activation of NF-κB and p53 in proximal tubular cells. 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 kidneys.