Abstract
The intestines are recognized as the main source of chronic inflammation in chronic kidney disease (CKD) and, among other cells, macrophages are involved in modulating this process as well as in the impaired immune response which also occurs in CKD patients. In this study, we evaluated the effect of Indoxyl Sulfate (IS), a protein bound uremic toxin poorly eliminated by hemodialysis, on inflammatory, oxidative stress and pro-apoptotic parameters, at the intestinal level in mice, on intestinal epithelial cells (IEC-6) and on primary murine peritoneal macrophages. C57BL/6J mice were treated with IS (800 mg/kg i.p.) for 3 or 6 h and histopathological analysis showed that IS induced intestinal inflammation and increased cyclooxygenase-2 (COX-2), nitrotyrosine and Bax expression in intestinal tissue. In IEC-6 cells, IS (125–1000 µM) increased tumor necrosis factor-α levels, COX-2 and inducible nitric oxide synthase expression and nitrotyrosine formation. Moreover, IS increased pro-oxidant, pro-inflammatory and pro-apoptotic parameters in peritoneal macrophages from IS-treated mice. Also, the serum concentration of IS and pro-inflammatory levels of cytokines resulted increased in IS-treated mice. Our results indicate that IS significantly contributes to affect intestinal homeostasis, immune response, and to induce a systemic pro-inflammatory state thus highlighting its potential role as therapeutic target in CKD patients.
Highlights
Chronic kidney disease (CKD) is associated with a persistent systemic inflammation and acquired immunodeficiency which promote the pathogenesis of many CKD-associated complications as leading causes of death [1,2,3]
The previous view that the intestine is a largely inert organ has been deeply changed and accumulating evidence highlighted that a chronic inflammatory state is a nontraditional risk factor in CKD patients and indicated that the gastrointestinal tract plays a pivotal role in systemic inflammation occurring in these patients [7,8]
Intestinal inflammation can be further promoted by macrophages, through proinflammatory cytokine production [51], we studied the status of peritoneal macrophages from indoxyl sulfate (IS)-treated mice
Summary
Chronic kidney disease (CKD) is associated with a persistent systemic inflammation and acquired immunodeficiency which promote the pathogenesis of many CKD-associated complications as leading causes of death [1,2,3]. Levels of circulating endotoxin increase with the severity of CKD stage and are most elevated in chronic hemodialysis and peritoneal dialysis patients [11,12]. A pivotal role in CKD-associated complications is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by healthy kidneys. These metabolites, called “uremic toxins”, have harmful effects in various physiological functions in CKD patients including immune response impairment [14,15,16,17,18,19] and intestinal homeostasis alterations. IS has been considered a nephro-vascular toxin that causes nephrotoxicity especially on tubular cells, inhibits proliferation of endothelial cells [21,22,23] but it is involved in other CKD-associated complications such as neurodegeneration [24,25]
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