microRNA Regulation of Acute Kidney Injury

Date

2011-08

Authors

Bhatt, Kirti

Journal Title

Journal ISSN

Volume Title

Publisher

Georgia Health Sciences University

Abstract

Acute kidney injury (AKI) is caused by an injury or insult to the kidneys resulting in abrupt loss of renal function. Acute kidney injury is a highly prevalent disease characterized by high rates of morbidity and mortality mainly due to the absence of effective therapeutic options. Dissecting the molecular basis of AKI is vital not only for understanding the mechanisms of disease pathogenesis, but also for designing effective treatments. The small regulatory non-coding RNAs, microRNAs, are vital regulators of normal cellular function and critical modulators of various pathological conditions. An intense focus has recently emerged on the study of microRNA regulation in the maintenance of kidney function and the development of renal diseases. Our laboratory demonstrated the first evidence that microRNAs play a pathogenic role during ischemia-induced AKI by utilizing a conditional Dicer knockout mouse model. The focus of my work was to identify and functionally characterize novel microRNAs that contribute to AKI. Firstly, using a cisplatin-induced nephrotoxicity model of AKI, we showed that miR-34a is up-regulated in a p53 dependent manner and contributes to renal cell survival. Secondly, we identified a novel microRNA, miR-687, as the most significantly upregulated microRNA during ischemia-induced AKI. Mechanistic studies showed that miR-687 is up-regulated in a hypoxia-inducible factor 1 (HIFl)-dependent manner and 3 subsequently negatively regulates PTEN expression under hypoxic conditions. These studies have unearthed an important HIFl-miR-687-PTEN signaling pathway that regulates cell cycle progression during hypoxia. Thirdly, we show that inhibiting miR- 687 significantly ameliorates ischemia-induced AKI. These studies have identified a pivotal signaling mechanism involved in cellular response to hypoxia that may be targeted for renoprotection during ischemic AKI.

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Keywords

Acute Kidney Injury, Dicer, Hypoxia, Hypoxia inducible factor-1 (HIF1), microRNA (miRNA), Nephrotoxicity, Phosphatase and tennis homolog (PTEN), Renal cell death

Citation

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