LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy
BackgroundDiabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN.MethodsDN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.895360/full |
| _version_ | 1811241384416378880 |
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| author | Panai Song Panai Song Yinyin Chen Zhiwen Liu Zhiwen Liu Hong Liu Hong Liu Li Xiao Li Xiao Lin Sun Lin Sun Jiali Wei Liyu He Liyu He |
| author_facet | Panai Song Panai Song Yinyin Chen Zhiwen Liu Zhiwen Liu Hong Liu Hong Liu Li Xiao Li Xiao Lin Sun Lin Sun Jiali Wei Liyu He Liyu He |
| author_sort | Panai Song |
| collection | DOAJ |
| description | BackgroundDiabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN.MethodsDN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo.ResultsMALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN.ConclusionMALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN. |
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| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-12T13:35:23Z |
| publishDate | 2022-06-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-4bdf6a603b974da8a4a5032e5e283b382022-12-22T03:31:01ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-06-011310.3389/fendo.2022.895360895360LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic NephropathyPanai Song0Panai Song1Yinyin Chen2Zhiwen Liu3Zhiwen Liu4Hong Liu5Hong Liu6Li Xiao7Li Xiao8Lin Sun9Lin Sun10Jiali Wei11Liyu He12Liyu He13Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaDepartment of Nephrology, Hunan Provincial People’s Hospital, Changsha, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaDepartment of Nephrology, Hainan General Hospital, Haiko, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaHunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, ChinaBackgroundDiabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN.MethodsDN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo.ResultsMALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN.ConclusionMALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN.https://www.frontiersin.org/articles/10.3389/fendo.2022.895360/fullLIN28Adiabetic nephropathyrenal tubular injuryAMPK/mTOR signalingMALAT1 |
| spellingShingle | Panai Song Panai Song Yinyin Chen Zhiwen Liu Zhiwen Liu Hong Liu Hong Liu Li Xiao Li Xiao Lin Sun Lin Sun Jiali Wei Liyu He Liyu He LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy Frontiers in Endocrinology LIN28A diabetic nephropathy renal tubular injury AMPK/mTOR signaling MALAT1 |
| title | LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy |
| title_full | LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy |
| title_fullStr | LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy |
| title_full_unstemmed | LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy |
| title_short | LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy |
| title_sort | lncrna malat1 aggravates renal tubular injury via activating lin28a and the nox4 ampk mtor signaling axis in diabetic nephropathy |
| topic | LIN28A diabetic nephropathy renal tubular injury AMPK/mTOR signaling MALAT1 |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.895360/full |
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