Mir-489 and mir-668 regulation during ischemic kidney injury

Tissue ischemia is a major cause of myocardial infarction and stroke in the brain. In kidneys, ischemia leads to acute kidney injury (AKI), which is also associated with high mortality. Despite decades of research, effective therapies for ischemic AKI are not available. MicroRNAs are a group of endogenous small non-coding RNAs that have been implicated in gene regulation in a variety of patho-physiological conditions. However, very limited is known for microRNA regulation in renal cells and tissues. Using a conditional Dicer-knockout mouse model, our latest study has demonstrated the first evidence for a role of microRNAs in ischemic AKI. Yet, whether and how these specific microRNAs contribute to ischemic AKI remain unknown. Our new preliminary data suggest that mir-489 and mir-668, two microRNAs induced by ischemic AKI, may regulate beta-catenin, a transcription regulatory protein that has recently been implicated in the regulation of renal cell injury. At the upstream level, we demonstrated mir-489 and mir-668 induction by hypoxia in cultured renal proximal tubular cells and the potential regulation of both mir-489 and mir-668 by HIF (Hypoxia-inducible factor). Based on these findings, we hypothesize that mir-489 and mir-668 are induced via HIF during renal hypoxia and ischemia/reperfusion and regulate ischemic AKI by targeting beta-catenin. We will determine the role of mir-489 and mir-668 in beta-catenin regulation during renal hypoxia and ischemia/reperfusion, determine the role of HIF-1 in mir-489 and mir-668 up-regulation, and determine the role of beta-catenin in renal ischemia-reperfusion injury in vivo. (AHA Program: Scientist Development Grant)