Abstract
Macrophages (MΦ) play an important role in acute rejection after kidney transplantation (Tx). Calcineurin inhibitor minimizing strategies may be associated with improved outcome after Tx. We sought to determine the role of a new protease inhibitor (PI, Ixazomib citrate, MLN9708) on MΦand MΦ associated genes in a CNI minimization strategy. Lewis (RT1l) recipients were transplanted with a full MHC mismatch Brown Norway (RT1n) rat kidney. Recipients were randomized into four groups: Control Brown Norway (C), Transplant with no treatment (Tx), transplant with full dose CsA (Tx, 10 mg/kg/d) or transplant with MLN9708 + half dose CsA (TxMLNCsA, 5 mg/kg/d). One week post-transplant, RNA was isolated from kidney for gene microarray analysis on Affymetrix Rat ST 2.0 chips. Differentially expressed gene (DEG) and pathway analyses were performed using iReport. Cellular analyses were performed using immunohistochemistry. Tx alone animals had a strong influx of MΦ into the kidney. Treatment with full dose CsA or low dose CsA + MLN9708 greatly reduced MΦ infiltration. The molecular signature associated with MΦ activation pathways was downregulated in animals treated with MLN9708 + ½ CsA, similar to full dose CsA.Table: No Caption available.These genes included IL-10, heme oxygenase 1 and biomarkers of M1 (iNOS) and M2 (arg1, CD163) MΦ phenotypes. These preclinical studies suggest that CNI minimization strategies with novel proteasome inhibitors may be effective in preventing macrophage-induced allograft injury. Further studies are needed to better characterize the significance and regulation of macrophage associated genes by proteasome inhibitors.
Published Version
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