Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells.

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 sulfateon expression of ICAM-1was 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-1in the kidneys compared with DN rats. DH + IS rats showed significantly increased mRNA expression of ICAM-1in the kidneys compared with DH rats. Immunohistochemistry revealed that ICAM-1was localized in the cytoplasm of renal tubular cells, and was most prominently expressed in DH + IS rats. Indoxyl sulfateupregulated mRNA and protein expression of ICAM-1in 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-1mRNA and protein in HK-2 cells. Significance Indoxyl sulfateupregulated renal expression of ICAM-1through production of reactive oxygen species (ROS) such as superoxide, and activation of NF-κB and p53 in proximal tubular cells. Further, administration of indoxyl sulfatepromoted ICAM-1expression in rat kidneys. Thus, accumulation of indoxyl sulfatein chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of ICAM-1in the kidney.