Long noncoding RNA KCNQ1OT1 induces pyroptosis in diabetic corneal endothelial keratopathy

Abstract

Diabetic corneal endothelial keratopathy is an intractable ocular complication characterized by corneal edema and endothelial decompensation, which seriously threaten vision. It has been suggested that diabetes is associated with pyroptosis, a type of programmed cell death via the activation of inflammation. Long noncoding RNA KCNQ1OT1 is commonly associated with various pathophysiological mechanisms of diabetic complications, including diabetic cardiomyopathy and diabetic retinopathy. However, whether KCNQ1OT1 is capable of regulating pyroptosis and participates in the pathogenesis of diabetic corneal endothelial keratopathy remains unknown. The aim of this study was to investigate the mechanisms of KCNQ1OT1 in diabetic corneal endothelial keratopathy. Here, we reveal that KCNQ1OT1 and pyroptosis can be triggered in diabetic human and rat corneal endothelium, along with the high glucose-treated corneal endothelial cells. However, miR-214 expression was substantially decreased in vivo and in experiments with cultured cells. LDH assay was also used to verify the existence of pyroptosis in high glucose-treated cells. Bioinformatics prediction and luciferase assays showed that KCNQ1OT1 may function as a competing endogenous RNA binding miR-214 to regulate the expression of caspase-1. To further analyze the KCNQ1OT1-mediated mechanism, miR-214 mimic and inhibitor were introduced into the high glucose-treated corneal endothelial cells. The results showed that upregulation of miR-214 attenuated pyroptosis; conversely, knockdown of miR-214 promoted it. In addition, KCNQ1OT1 knockdown by a small interfering RNA decreased pyroptosis factors expressions but enhanced miR-214 expression in corneal endothelial cells. To understand the signaling mechanisms underlying the prepyroptotic properties of KCNQ1OT1, si-KCNQ1OT1 was cotransfected with or without miR-214 inhibitor. The results showed that pyroptosis was repressed after silencing KCNQ1OT1 but was reversed by cotransfection with miR-214 inhibitor, suggesting that KCNQ1OT1 mediated pyroptosis induced by high glucose via targeting miR-214. Therefore, the KCNQ1OT1/miR-214/caspase-1 signaling pathway represents a new mechanism of diabetic corneal endothelial keratopathy progression, and KCNQ1OT1 could potentially be a novel therapeutic target.

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

“…Diabetic corneal endothelial keratopathy is an intractable ocular complication which seriously threatens vision. It has been suggested that diabetes is associated with pyroptosis, long noncoding RNA (lncRNA)KCNQ1 overlapping transcript 1 (KCNQ1OT1) triggers NLRP3 inflammasome activation and caspase1-mediated pyroptosis via targeting miR-214 induced by high glucose in diabetic human and rats' corneal endothelium [68]. Inflammasome could contribute to ischemic brain injury by inducing inflammation and pyroptosis.…”

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

“…miR-34a suppressed metastasis of human cancers by targeting specific genes, including YY1 in liver cancer [ 151 ], CCL22 in renal cell carcinoma [ 152 ], CD44 in osteosarcoma cells [ 153 ], and prostate cancers [ 154 ]. Kcnq1ot1 miR-214-3p miR-486a-3p LncRNA Kcnq1ot1 induced pyroptosis in diabetic corneal endothelial kerotopathy [ 155 ]. Kcnq1ot1 induced pyroptosis was due to inhibiting miR-486a-3p and upregulating NLRP3 [ 156 ].…”

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

“…Previous reports indicate that METTL3 regulates multiple cell functions and diseases by modulating N 6 -methyladenosine (m 6 A) modifications. [189][190][191] 192 The authors suggest that the KCNQ1OT1/miR-214/caspase-1 signaling pathway shows a novel diabetic corneal endothelial keratopathy progression and can be a promising therapeutic target in the future. 192 In addition, increasing evidence suggests that vitamin D3 has substantial therapeutic effects in treating DR. 193 Vitamin D3 administration can significantly protect against DR by inhibiting the HG-induced ROS/TXNIP/ NLRP3 inflammasome signaling pathway.…”

“…[189][190][191] 192 The authors suggest that the KCNQ1OT1/miR-214/caspase-1 signaling pathway shows a novel diabetic corneal endothelial keratopathy progression and can be a promising therapeutic target in the future. 192 In addition, increasing evidence suggests that vitamin D3 has substantial therapeutic effects in treating DR. 193 Vitamin D3 administration can significantly protect against DR by inhibiting the HG-induced ROS/TXNIP/ NLRP3 inflammasome signaling pathway. 194 Methylene blue (MB) administration can tremendously attenuate DR by impeding the NLRP3 inflammasome activation in STZtreated diabetic rats.…”