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      LncRNA PVT1 Suppresses the Progression of Renal Fibrosis via Inactivation of TGF-β Signaling Pathway

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          Abstract

          Background

          Renal fibrosis is a frequent pathway leading to end-stage kidney dysfunction. In addition, renal fibrosis is the ultimate manifestation of chronic kidney diseases (CKD). Long noncoding RNAs (lncRNAs) are known to be involved in occurrence of renal fibrosis, and lncRNA plasmacytoma variant translocation 1 (PVT1) has been reported to act as a key biomarker in renal diseases. However, the role of PVT1 in renal fibrosis remains unclear.

          Materials and Methods

          HK-2 cells were treated with TGF-β1 to mimic renal fibrosis in vitro. Gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of creatinine (CR) and blood urea nitrogen (BUN) in serum of mice. Additionally, unilateral ureteral obstruction (UUO)-induced renal fibrosis mice model was established to investigate the effect of PVT1 on renal fibrosis in vivo.

          Results

          PVT1 was upregulated in TGF-β1-treated HK-2 cells. In addition, TGF-β1-induced upregulation of α-SMA and fibronectin in HK-2 cells was significantly reversed by PVT1 knockdown. Meanwhile, PVT1 bound to miR-181a-5p in HK-2 cells. Moreover, miR-181a-5p directly targeted TGF-βR1. Furthermore, miR-181a-5p antagonist could significantly reverse the anti-fibrotic effect of PVT1 knockdown. Besides, knockdown of PVT1 notably attenuated the symptom of renal fibrosis in vivo.

          Conclusion

          Knockdown of PVT1 significantly inhibited the progression of renal fibrosis in vitro and in vivo. Thus, PVT1 may serve as a potential target for the treatment of renal fibrosis.

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          Most cited references 45

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          Long non-coding RNA PVT1 promote LPS-induced septic acute kidney injury by regulating TNFα and JNK/NF-κB pathways in HK-2 cells.

          This study aimed to investigate the effect and underlying mechanism of long non-coding RNA plasmacytoma variant translocation 1 (PVT1) in lipopolysaccharide (LPS)-induced inflammation injury in HK-2 cells. We established LPS-induced septic acute kidney injury (AKI) model in HK-2 cells. LPS-induced HK-2 cells were transfected with pc-PVT1, pc-NC, si-PVT1 or si-NC. Cell viability and apoptosis rate were detected by MTT assay and Annexin V-FITC/PI Apoptosis Detection kit, respectively. The relationships of PVT1 and inflammatory factors were evaluated by RNA Immunoprecipitation (RIP) assay. The levels of inflammatory factors, apoptosis-related proteins and the expressions of proteins related to c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) signaling pathway were detected by ELISA or Western blotting. Compared with cells with pc-NC, cell viability was remarkably decreased and cell apoptosis rate was increased in LPS-induced cells with pc-PVT1 (p<0.05). The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β were significantly increased in LPS-induced cells with pc-PVT1 compared with cells with pc-NC (p<0.05). All these changes were reversed in LPS-induced cells with si-PVT1 and si-NC (p<0.05). RTP assay revealed that PVT1 could bind to TNF-α. Furthermore, down-regulated PVT1 remarkably reduced the expressions of p-JNK and p-c-Jun, p-IκBα and p-p65 (p<0.05); while increased expressions of these proteins and inflammatory factors induced by up-regulated PVT1 were reversed by JNK or NF-κB inhibitors. PVT1 may promote inflammatory response by binding to TNF-α and inhibiting JNK/NF-κB signaling pathway in LPS-induced septic AKI cells.
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            Long non‑coding RNA PVT1 promotes epithelial‑mesenchymal transition via the TGF‑β/Smad pathway in pancreatic cancer cells.

            Recent studies have revealed that overexpression of long non‑coding RNA (lncRNA) PVT1 is correlated with several types of cancer. However, its role in pancreatic cancer development remains to be clarified. In the present study, we found that PVT1 promoted the growth and the epithelial‑mesenchymal transition (EMT) of pancreatic cancer cells. We first determined that PVT1 was upregulated in pancreatic cancer tissues compared with adjacent normal tissues. Knockdown of PVT1 inhibited viability, adhesion, migration and invasion. Furthermore, PVT1 knockdown reduced the expression of mesenchymal markers including Snail, Slug, β‑catenin, N‑cadherin and vimentin, while it increased epithelial marker expression of E‑cadherin. Finally, knockdown of PVT1 inhibited the TGF‑β/Smad signaling, including p‑Smad2/3 and TGF‑β1 but enhanced the expression of Smad4. In contrast, overexpression of PVT1 reversed the process. These findings revealed that PVT1 acts as an oncogene in pancreatic cancer, possibly through the regulation of EMT via the TGF‑β/Smad pathway and PVT1 may serve as a potential target for diagnostics and therapeutics in pancreatic cancer.
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              LncRNA PVT1 regulates atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation

              Background Long non-coding RNAs (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been shown to be associated with liver fibrosis. Nevertheless, the role of PVT1 in atrial fibrosis remains undefined. This study aims to elucidate the pathophysiological role of lncRNA PVT1 in the regulation of atrial fibrosis and to explore the underlying mechanism. Methods Expression of PVT1, miR-128-sp, and Sp1 were examined in human atrial muscle tissues and angiotensin-II (Ang-II)-induced human atrial fibroblasts. Furthermore, the role of PVT1 in regulating atrial fibrosis in Ang-II-treated human atrial fibroblasts and Ang-II-induced atrial fibrosis in mice was investigated. Moreover, the interaction among PVT1, miR-128-3p, and Sp1 were examined using bioinformatics, expression correlation analysis, gain- or loss-of-function assays, RIP assays, and luciferase reporter assays. The involvement of transforming growth factor beta 1 (TGF-β1)/Smad pathway in this process was also explored. Results PVT1 was increased in atrial muscle tissues from AF patients and positively with collagen I and collagen III. In vitro assay revealed that PVT1 overexpression facilitated the Ang-II-induced atrial fibroblasts proliferation, collagen production, and TGF-β1/Smad signaling activation, whereas PVT1 knockdown caused the opposite effect. In vivo assay further confirmed that PVT1 knockdown attenuated the Ang-II-induced mouse atrial fibrosis. Mechanically, PVT1 acted as a sponge for miR-128-3p to facilitate Sp1 expression, thereby activating the TGF-β1/Smad signaling pathway. Conclusion LncRNA PVT1 promotes atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation. Electronic supplementary material The online version of this article (10.1186/s10020-019-0074-5) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                26 August 2020
                2020
                : 14
                : 3547-3557
                Affiliations
                [1 ]Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan 450000, People’s Republic of China
                [2 ]Department of Cancer Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou, Henan 450000, People’s Republic of China
                Author notes
                Correspondence: Lu Cao Email caolu_mailtowe@163.com
                Article
                245244
                10.2147/DDDT.S245244
                7457787
                © 2020 Cao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, References: 48, Pages: 11
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                tgf-βr1, pvt1, mir-181a-5p, renal fibrosis

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