The regulation and function of long non coding RNA in ischemic AKI: Role of GSTM3P1

Summary: Acute kidney injury (AKI) is a major renal disease that can be caused by ischemia, sepsis, urinary obstruction and nephrotoxins. It is associated with high mortality clinically and may further lead to chronic kidney diseases (CKD). Kidney ischemia is one of the leading causes of AKI. It can result from massive heart attack, blood vessel

dysfunction, major cardiac surgery, or other cardiovascular diseases. One of the critical barriers to progress is how to improve the AKI survival rate, which is closely related to the limited understanding of the regulation of renal tubular cell death and lack of treatment to prevent renal tubular death. The goal of this application is to

investigate the pathogenic function and regulation of long non-coding RNA (lncRNA) with GSTM3P1 as an example to study the related pathways in renal tubular cell death and to identify new strategies for AKI therapy. Recent studies identified lncRNAs as critical novel regulators of kidney diseases including AKI. Our focus on

GSTM3P1 is based on (1) we identified GSTM3P1 as a top lncRNA to interact with renal protective microRNAs (miRNA) (mir-489 and mir-668) in RNA induced silencing complex, suggesting GSTM3P1 as an excellent example to study the novel regulation mechanism between miRNA and lncRNA; (2) our preliminary studies

indicate potential induction and strong injurious effect of GSTM3P1 during ischemic AKI and the further understanding of its detailed function and regulation may significantly help AKI therapy development by using lncRNAs as targets; (3) we also found potential inhibition of GSTM3 by GSTM3P1 and the understanding of the

underlying mechanism will provide new information for lncRNA and pseudogene function. Our central hypothesis is that GSTM3P1 is induced during kidney ischemia to cause kidney injury by inhibition of renal protective factors, such as mir-668 and GSTM3. Our objective is to identify new therapeutic targets (GSTM3P1,

GSTM3) for AKI treatment. We will test the hypothesis by three aims. Aim1: Test the hypothesis that GSTM3P1 increases during ischemic AKI to induce renal tubular injury. Aim2: Test the hypothesis that GSTM3P1 interacts with mir-668 and causes mir-668 decay to induce kidney injury. Aim3: Test the hypothesis that GSTM3P1 can

induce kidney injury through the inhibition of GSTM3. Our expect outcomes include: (1) identifying GSTM3P1 and GSTM3 as new therapeutic targets for AKI; (2) extending the knowledge of lncRNA function in AKI, (3) extending the knowledge of regulation between lncRNA and miRNA; (4) extending the knowledge of protein

expression regulation by lncRNAs. Our findings will have impact on (1) the AKI research field by elucidating the pathological role of lncRNA GSTM3P1 and its downstream regulation of mir-668 and GSTM3; and (2) the other medical research fields for the novel understanding of interaction between miRNA and lncRNA and protein

expression regulation by lncRNA from pseudogene.