Uremic Toxins Are Conditional Danger-or Homeostasis-associated Molecular Patterns

Objective:We aimed to study the mechanism of CKD-mediated accumulation of endogenous metabolites referred to as uremic toxins(UT),and verified whether these uremic toxins serve as endogenous metabolite-derived danger signals to activate DAMPs receptors,as well as how these metabolites are modulated in patients.Methods:We performed novel UT metabolomics/gene database mining,where we identified protein-bound UT receptors as well as the enzymes for UT generation,and analyzed their gene expression changes in CKD,vascular and metabolic diseases.Results:We made the following findings: 1)In CKD,UTs represent a very small fraction of the total human serum small-molecule metabolome,roughly 1/80th;2)The serum concentrations of some UTs are increased not only in CKD but in other diseases;3)Protein-bound UTs either induce or suppress the expression of pro-inflammatory molecules;4)The expression of UT genes is significantly modulated in the tubules of CKD patients,and adipose tissue of coronary artery disease(CAD)patients,compared with those of metabolic syndrome and type 2 diabetes patients;5)The expression of UT genes is upregulated by caspase-1 and TNF-α pathways,more than toll-like receptors(TLRs),IL-1β and IFN-pathways;and 6)The expression of UT genes is inhibited in regulatory T cells.20% of free form uremic toxins are pro-inflammatory and 12% of them are anti-inflammatory.14% of the protein-bound uremic toxins are pro-inflammatory and 5% of them are anti-inflammatory.19.52% of uremic toxin related genes are upregulated and 33.14% of them are downregulated in metabolic diseases.Conclusion:Our results have demonstrated that UTs are selectively increased rather than by purely passive accumulation;and UTs serve as danger signal-associated molecular patterns(DAMPs)and homeostasis-associated molecular patterns(HAMPs)that modulate inflammation.In addition,our results show that some UT genes are upregulated in CKD and CAD,presumably via caspase-1/inflammatory cytokine pathways.