miR-1247 blocks SOX9-mediated regeneration in alcohol- and fibrosis-associated acute kidney injury in mice.
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abstract
Excessive alcohol consumption has a significant impact on human health and is a major public health problem worldwide. One of the consequences of long-term excessive alcohol consumption is cellular injury in almost all organs and tissues, with acute kidney injury (AKI) being one of the most common pathological manifestations. In the present study, using a mouse model of alcoholic liver fibrosis-associated AKI induced by a combined treatment with carbon tetrachloride (CCl4) and ethanol and resembling pathological features of AKI in human alcoholic liver fibrosis, we demonstrate alterations in histone modifications in the kidneys and, importantly, in the promoter region of the over-expressed SRY (sex determining region Y)-box 9 (Sox9) gene. The level of SOX9 protein in the kidneys of AKI-mice is reduced and correlates inversely with increased expression of microRNA miR-1247. Mechanistically, the over-expression of miR-1247 is associated with a markedly increase in histone H3 lysine 4 trimethylation in the upstream region of the Mir1247 gene. The results of the present study demonstrate a functional role of epigenetic mechanisms in AKI and indicate the importance of correcting the epigenetic dysregulation for proper renal tubule maintenance and repair.
