Uremic solutes of indoxyl sulfate and p-cresol enhance protease-activated receptor-2 expression in vitro and in vivo in keratinocytes

Abstract

Objectives: Uremic pruritus is common in patients with chronic kidney disease (CKD). The retention of uremic solutes is thought to be associated with uremic pruritus. Meanwhile, activation of protease-activated receptor-2 (PAR-2) has been suggested to play an important role in pruritus. The present study was performed to investigate the effects of uremic solutes on the expression of PAR-2 in the skin. Methods: Indoxyl sulfate (IS), p-cresol (PC), and uremic sera from CKD patients were used to stimulate PAR-2 expression in normal human epidermal keratinocytes (NHEKs). Also, NHEKs were additionally pretreated with soybean trypsin inhibitor to evaluate its inhibitory effect on PAR-2 expression. Patterns of cutaneous PAR-2 expression were investigated in skin samples from five CKD patients and CKD mice. Results: In NHEKs, IS, PC, and sera from CKD patients significantly induced PAR-2 mRNA and protein expression. Soybean trypsin inhibitor significantly decreased PAR-2 mRNA and protein expression in NHEKs treated with IS, PC, and CKD sera. NHEKs treated with IS and PC exhibited significant increases in protease activity. Skin from both CKD patients and mice exhibited marked upregulation of PAR-2 expression compared to control skin. Conclusions: Results from the present study suggest that uremic solutes either directly or indirectly affect PAR-2 expression in the skin of CKD subjects, potentially playing an important role in the pathogenesis of uremic pruritus.

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

“…Our results did not confirm the associations between uremic toxins and symptoms described previously in preclinical studies and in CKD cohorts [ 7–9 , 11 , 12 ]. This discrepancy may be partly due to the differences in the study population (e.g.…”

“…Even though symptoms have clinical significance, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. In one recent study, indoxyl sulfate (IS), p -cresol and uremic serum affected (either directly or indirectly) protease-activated receptor 2 expression in the skin of patients with CKD, suggesting that these compounds might have an important role in the pathogenesis of uremic pruritus [ 7 ]. In another study, total p -cresyl sulfate (PCS), but not IS, was independently associated with pruritus, after adjustment for known biomarkers [ 8 ].…”

Chronic Intractable Pruritus in Chronic Kidney Disease Patients: Prevalence, Impact, and Management Challenges — A Narrative Review

“…Both PBUTs and CKD induced PAR2 expression and upregulated PAR2 expression in skin samples taken from human and mouse CKD subjects compared to healthy controls. 46 Similarly, Moon et al 47 found significantly higher epidermal PAR2 expression in ESRD patients then in controls. In addition, a positive correlation between PAR2 expression and VAS pruritus scores was found.…”

Chronic Kidney Disease-Associated Pruritus: A Glance at Novel and Lesser-Known Treatments

“…Also, oral charcoal can affect the absorption of certain drugs given to patients, which has not been studied by many trials [53]. Charcoal seems to relieve pruritus by absorbing small molecules responsible for inducing the itch, such as indoxyl sulfate and p-Cresyl sulfate; these substances have been found to amplify protease-activated receptor-2 expression on the skin, which is linked to non-histaminergic itching [54]. The study also highlights the role of dysbiosis in CKD and its possible contribution to pruritus.…”