Macrophage Migration Inhibitory Factor Limits Renal Inflammation and Fibrosis by Counteracting Tubular Cell Cycle Arrest

Abstract

<p class="first" id="d3791811e243">Renal fibrosis is a common underlying process of progressive kidney diseases. We investigated the role of macrophage migration inhibitory factor (MIF), a pleiotropic proinflammatory cytokine, in this process. In mice subjected to unilateral ureteral obstruction, genetic deletion or pharmacologic inhibition of MIF aggravated fibrosis and inflammation, whereas treatment with recombinant MIF was beneficial, even in established fibrosis. In two other models of progressive kidney disease, global <i>Mif</i> deletion or MIF inhibition also worsened fibrosis and inflammation and associated with worse kidney function. Renal MIF expression was reduced in tubular cells in fibrotic compared with healthy murine and human kidneys. Bone marrow chimeras showed that <i>Mif</i> expression in bone marrow-derived cells did not affect fibrosis and inflammation after UUO. However, <i>Mif</i> gene deletion restricted to renal tubular epithelial cells aggravated these effects. In LPS-stimulated tubular cell cultures, <i>Mif</i> deletion led to enhanced G2/M cell-cycle arrest and increased expression of the CDK inhibitor 1B (p27Kip1) and of proinflammatory and profibrotic mediators. Furthermore, MIF inhibition reduced tubular cell proliferation <i>in vitro</i>. In all three <i>in vivo</i> models, global <i>Mif</i> deletion or MIF inhibition caused similar effects and attenuated the expression of cyclin B1 in tubular cells. <i>Mif</i> deletion also resulted in reduced tubular cell apoptosis after UUO. Recombinant MIF exerted opposing effects on tubular cells <i>in vitro</i> and <i>in vivo</i>. Our data identify renal tubular MIF as an endogenous renoprotective factor in progressive kidney diseases, raising the possibility of pharmacologic intervention with MIF pathway agonists, which are in advanced preclinical development. </p><p class="first" id="d3791811e277"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/8c21bbd6-3419-4a95-8bec-6a14aa6d187a/PubMedCentral/image/ASN.2017020190absf1"/> </div> <div class="panel-content"/> </div> </p>