Sesquiterpene Lactones Inhibit Advanced Oxidation Protein Product-Induced MCP-1 Expression in Podocytes via an IKK/NF-κB-Dependent Mechanism

Inflammation is a relevant factor in the pathogenesis of diabetes nephropathy (DN). Sesquiterpene lactones (SLs), originally isolated from Tanacetum parthenium, have been reported to exhibit anti-inflammatory effects but few studies have examined their effects on DN. To determine whether advanced oxidation protein products (AOPPs) can induce the expression of chemokine monocyte chemoattractant protein- (MCP-) 1 in cultured mouse podocytes and to explore the mechanisms of the potential renoprotection of SLs, we treated podocytes with AOPPs and SLs (parthenolide and its derivatives micheliolide, compound 1, and compound 2). MCP-1mRNA and protein expression were tested using quantitative real-time PCR and ELISA, respectively, and the protein levels of IKK beta, phospho-IKK beta, I kappa B alpha, NF-kappa B p65, phospho-NF-kappa B p65, and tubulin were analyzed by Western blotting. AOPPs activated the expression of MCP-1 mRNA and protein in a dose- and time-dependent manner, activated IKK beta and NF-kappa B p65, and promoted I kappa B alpha degradation. The IKK/NF-kappa B inhibitor parthenolide decreased AOPP-induced MCP-1 expression. Pretreatment with SLs inhibited MCP-1 mRNA and protein expression and suppressed IKK beta and NF-kappa B p65 phosphorylation and I kappa B alpha degradation. Taken together, these findings provide a novel explanation for the anti-inflammatory effects of SLs that will ultimately benefit DN and potentially other inflammatory and immune renal diseases.