Project title
微小核醣核酸調控肝抑鐵素-調節鐵調素傳導路徑在急性腎損傷後影響鐵平衡之研究
Internal ID
MOST104-2314-B002-125-MY3
Principal Investigator
Start Date
August 1, 2015
End Date
July 12, 2016
Investigators
Organizations
Partner Organizations
Project Web Site
Novel microRNAs Modulates Hemojuvelin-Hepcidin Pathway on Iron Homeostasis during Acute Kidney Injury = 微小核醣核酸調控肝抑鐵素-調節鐵調素傳導路徑在急性腎損傷後影響鐵平衡之研究
Keywords
HJV-BMP-hepcidin
TMPRSS6
Furin
microRNA
AKI
kidney
Description
Novel microRNAs modulates hemojuvelin-hepcidin pathway on iron homeostasis during acute kidney injury The incidence rate of acute kidney injury (AKI) in hospitalized patients is increasing, and the number of deaths associated with dialysis-requiring AKI has more than doubled. In hospitalized patients, AKI results in increased in-hospital and post-hospitalization resource utilization. Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-BMP-hepcidin axis. Hepcidin excess results in impaired iron absorption and impaired ability to utilize iron that has been reclaimed by macrophages during I/R AKI. Hemojuvelin (HJV), furin and TMPRSS6 play an essential role in the regulation of hepcidin expression and affect the iron deposition during AKI. miRNAs have been demonstrated to post-transcriptionally regulate the expression of genes associated with iron acquisition, iron export, iron storage, iron utilization, and coordination of systemic iron homeostasis. However, the miRNAs modulating hemojuvelin-hepcidin signaling pathway during AKI has not been elucidated. Accordingly, we have identified the miRNAs, regulating hemojuvelin-BMP-hepcidin signaling pathway, from human kidney specimens at AKI by using miRNA array chip. The well-fitted conserved motif of 3’-UTR of HFE2 (HJV), TMPRSS6 and Furin as the target contains a matching with the ‘seed’ sequence of candidate microRNA are predicted by StarBase program analysis Therefore, the goals of this proposal will (1) To identify and validate the candidate miRNAs from humans specimen, especially miR-187, miR-665, and miR-137 and miR-122, by real-time quantitative reverse transcriptase polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) and immunohistochemistry. (2) To investigate the molecular role of hemojuvelin-hepcidin pathway-related miRNAs in the regulation of hepcidin expression and affects the iron deposition in cell model under hypoxia/iron overload. (3) To investigate the effect of HJV-BMP-hepcidin pathway-related miRNAs on furin protease, TMPRSS6, hepcidin, and the ratio of mHJV/sHJV in animal model and clinical using as a novel biomarker of AKI using the database from NSARF/CAKS. This study aimed to understand the mechanism of HJV-mediated iron sensing pathway during AKI, regulating by miRNAs through HJV/ Furin and TMPRSS6 signaling. We will show for the first time to our knowledge that systemic iron homeostasis, modulated by HJV is also controlled by miRNAs. The candidate miRNAs will be potential novel biomarker for diagnosis and prognosis of AKI. Our result will shed light for further therapeutic strategies to rescue through modulating iron sensing HJV-BMP -hepcidin signaling.