Abstract
BackgroundOxidative stress and endoplasmic reticulum (ER) stress play a crucial role in tubular damage in both acute kidney injury (AKI) and chronic kidney disease (CKD). While the pathophysiological contribution of microRNAs (miRNA) to renal damage has also been highlighted, the effect of miRNA on renal damage under oxidative and ER stresses conditions remains elusive.MethodsWe assessed changes in miRNA expression in the cultured renal tubular cell line HK-2 under hypoxia-reoxygenation-induced oxidative stress or ER stress using miRNA microarray assay and real-time RT-PCR. The pathophysiological effect of miRNA was evaluated by cell survival rate, intracellular reactive oxygen species (ROS) level, and anti-oxidant enzyme expression in miRNA-inhibited HK-2 or miRNA-overexpressed HK-2 under these stress conditions. The target gene of miRNA was identified by 3′-UTR-luciferase assay.ResultsWe identified 8 and 10 miRNAs whose expression was significantly altered by oxidative and ER stresses, respectively. Among these, expression of miR-205 was markedly decreased in both stress conditions. Functional analysis revealed that decreased miR-205 led to an increase in cell susceptibility to oxidative and ER stresses, and that this increase was associated with the induction of intracellular ROS and suppression of anti-oxidant enzymes. While increased miR-205 by itself made no change in cell growth or morphology, cell viability under oxidative or ER stress conditions was partially restored. Further, miR-205 bound to the 3′-UTR of the prolyl hydroxylase 1 (PHD1/EGLN2) gene and suppressed the transcription level of EGLN2, which modulates both intracellular ROS level and ER stress state.ConclusionsmiR-205 serves a protective role against both oxidative and ER stresses via the suppression of EGLN2 and subsequent decrease in intracellular ROS. miR-205 may represent a novel therapeutic target in AKI and CKD associated with oxidative or ER stress in tubules.
Highlights
Tubular cells are the main target of acute kidney injury (AKI)
MiRNA Expression Profile in HK-2 Under Oxidative Stress MiRNA expression profiles under oxidative stress were evaluated by assessing changes in miRNA expression by miRNA microarray analysis in a human proximal tubular cell line, HK-2, exposed to hypoxia-reoxygenation
Down-regulation of miR-205 suppressed the stress induced-increase of these anti-oxidant enzymes (Figure 7D–7G). These results revealed that modulation of miR-205 altered the expression of anti-oxidant enzymes, resulting in the impairment of cell survival. These results suggested that the basal expression level of miR-205 in HK-2 was sufficient to regulate intracellular reactive oxygen species (ROS) level, so that the effect of miR-205 overexpression via increase of anti-oxidant enzymes were exerted only when cells were under the stress conditions, namely when cells must be strongly protected against free radical damage by scavenging excessive ROS
Summary
Tubular cells are the main target of acute kidney injury (AKI). Reflecting the tubular cell damage, renal function is rapidly aggravated unless renal hypoperfusion or other causes of acute injury are promptly removed during the early, potentially reversible stage. The final common pathway in this process has been studied closely, and careful pathological analysis has revealed a good correlation between the degree of impairment of renal function in CKD and the extent of tubulointerstitial damage, indicating that tubular damage mediates the progression of chronic kidney disease (CKD). Among various insults that damage tubular cells in both AKI and CKD, recent studies have emphasized a role for pathogenic crosstalk between oxidative stress and endoplasmic reticulum (ER) stress. Hypoxia associated with oxidative stress in the kidney is both a central player in AKI as well as the final common pathway of CKD leading to end-stage kidney disease [3,4]. Oxidative stress and endoplasmic reticulum (ER) stress play a crucial role in tubular damage in both acute kidney injury (AKI) and chronic kidney disease (CKD). While the pathophysiological contribution of microRNAs (miRNA) to renal damage has been highlighted, the effect of miRNA on renal damage under oxidative and ER stresses conditions remains elusive
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