Abstract
Mounting evidence has indicated that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) played important roles in renal ischemia/reperfusion (I/R) injury. However, the involvement of lncRNA growth arrest specific 5 (GAS5) in acute kidney injury (AKI) remained largely unexplored. This study aimed to determine possible mechanisms of GAS5 in the renal I/R process. We found that GAS5, noticeably upregulated by renal I/R injury, was further suppressed by delayed IPC while knockdown of miR-21 in vivo before IPC could significantly increased the GAS5 levels. Concurrently, TSP-1 was negatively regulated by miR-21 in vivo and vitro. Additionally, Reciprocal repression of GAS5 and miR-21 was identified. Knockdown of miR-21 in H6R0.5 treated HK-2 cells promoted apoptosis. Co-transfection of miR-21 mimic and pcDNA-GAS5 or pcDNA-Vector were performed, results of which showed that inhibition of miR-21 on TSP-1 could be rescued by overexpression of GAS5. This study suggested that GAS5 facilitated apoptosis by competitively sponging miR-21, which negatively regulated TSP-1 in renal I/R injury. This novel regulatory axis could act as a therapeutic target for AKI in the future.
Highlights
Acute kidney injury (AKI) is a common complication characterized by a decline in renal function
We found that long noncoding RNAs (lncRNAs) growth arrest specific 5 (GAS5) might contribute to renal I/R injury due to its proapoptosis function[11]
The protein expression of TSP-1 was almost undetectable in Sham-operated kidneys, peaked at 12 h and decreased to the baseline level at 48 h of reperfusion, which was consistent with our RT-PCR results and similar to the results from Thakar’s study (Fig. 1f). miR-21 and TSP-1 in I/R (24 h) treated kidneys were expressed mainly in renal tubular epithelial cells, as shown in the In situ hybridization (ISH) results (Fig. 1e)
Summary
Acute kidney injury (AKI) is a common complication characterized by a decline in renal function. Renal ischemia/reperfusion (I/R) insult contributes greatly to AKI. Cell apoptosis is considered to be involved in pathogenesis of I/R injury. It has been reported that many mechanisms contribute to apoptosis regulation in renal tubular epithelial cells in the process of renal I/R1. Emerging evidence has shown that lncRNAs are involved in many biological processes by regulating gene expression at epigenetic, transcriptional, and post-transcriptional levels[6,7]. Hypoxia-regulated lncRNAs were identified in some tumor studies[8] and an effect of I/R on lncRNAs expression was uncovered as well[9]. Ectopic expression of lncRNA GAS5 was first found in hypoxia-treated renal tubular epithelial cells in Yu’s
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