Macrophage migration inhibitory factor is a novel biomarker, mediator, and therapeutic target for acute kidney injury via enhancing NF-κB-Syk-Mincle circuit

Ph.D. ; Objectives: Acute kidney injury (AKI) is a common and severe complication in the critically ill patients with poor clinical outcomes and a major cause of chronic kidney disease. However, mechanisms of AKI remain largely unclear and effective therapies for AKI remain to be developed. Macrophages have been recognized as a key player in AKI. We found that local and systemic MIF production is markedly increased in both human and experimental kidney diseases associated with abundant infiltrating macrophages and T cells. Blockade of MIF with neutralizing antibody and a novel inhibitor (RPS19) can inhibit or partially reverse renal injury in rapidly progressive crescentic glomerulonephritis, suggesting MIF as a key mediator in immunologically-induced kidney disease. Here, we further extended our previous findings of MIF in glomerulonephritis to AKI and performed mechanistic studies in ischemia–reperfusion injury (IRI) and cisplatin-induced mouse models of AKI in MIF knockout (KO) mice. This project will uncover the role and working mechanism of MIF in AKI. ; Methods: To investigate whether MIF participates in the development of AKI, serum and urinary levels of MIF from 43 AKI patients and 30 healthy controls were measured by ELISA, while expression of MIF mRNA from blood leukocytes was detected by real-time PCR. To explore the pathogenic role of MIF in AKI, AKI was induced in MIF knockout (KO) mice by ischemia/reperfusion injury (IRI) or cisplatin injection, their renal function and renal inflammation were examined. The pathogenic role of macrophage-derived MIF was demonstrated by adoptive transferring MIF KO or WT macrophages into mice with AKI. The mechanism of MIF in AKI was identified both IRI- and Cis-AKI models in vivo and in bone marrow-derived macrophages in vitro. To develop an effective therapy for AKI, renal protective effect of MIF inhibitor RPS19 was evaluated on mice with AKI. Protective effects and mechanisms of genetic deletion or pharmacological inhibition of MIF on AKI were also examined. ...