The clinical implication of macrophage migration inhibitory factor in acute kidney injury

摘要

Acute kidney injury (AKI) is associated with increase in-hospital morbidity and mortality Biomarkers to facilitate early identification of kidney injury and the strategies to prevent the development of AKI are of emergent needs Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and is constitutively expressed in renal tubules Under inflammatory kidney disease renal MIF upregulates and the level of renal MIF is correlated to leukocyte infiltration histopathological damage and renal dysfunction and is therefore considered as a potential marker and pathogenic participant for the development of renal injury Although kidney infection is an important factor to AKI the mechanism of renal MIF deregulation and pathogenic role of MIF during kidney infections remains unknown We therefore hypothesize that MIF acts as a pathogenic regulator and participate in the development of AKI The aim of our thesis is at investigating the clinical implication of aberrant MIF expression in detecting AKI and the pathogenic role of MIF in the development of AKI In Specific Aim 1 of this thesis the correlation between deregulated MIF and renal dysfunction were investigated through prospective clinical study enrolling patients with pyelonephritis We demonstrated that elevated levels of urine MIF accompanied the development of AKI An elevated urine MIF level along with elevated kidney injury molecule-1 and interleukin-1β levels is speculated to be a biomarker for the presence of AKI in patients with pyelonephritis To investigate the expression pattern of MIF during AKI we used a mice model of ascending urinary tract infections The urine MIF increased accompanying with the development of AKI and histological damage in mice model of kidney infections Notably the MIF storage of the renal cortical tubules diminished with AKI through unknown mechanism In Specific Aim 2 of this study we demonstrated that uropathogenic Escherichia coli infections caused necrotic cell death and accompanied with MIF release from intracellular storage Kidney infections cause vasculature damage and produce ischemia injury to the kidney Kidney ischemic injury is a major contributing factor to the development of AKI For Specific Aim 3 we investigated the pathogenic role of MIF in the development of ischemia-evoked AKI through mice models of kidney ischemia-reperfusion injury (IRI) Elevation of urine MIF was found in subclinical kidney damage in which serum creatinine were within normal limit Furthermore MIF inhibitions protected kidney against renal IRI-induced AKI tissue damage and renal inflammation Taken together the thesis demonstrated that measurement of urine MIF is a accessible assay for detect AKI and even subclinical kidney damage and MIF-targeting strategy may be an effective target against the development of AKI

獎項日期	2014 8月 20
原文	English
監督員	Chin-Chung Tseng (Supervisor)