bims-lorfki 2021-11-28 papers

Nephron. 2021 Nov 17. 1-11

The Long Noncoding RNA-H19 Mediates the Progression of Fibrosis from Acute Kidney Injury to Chronic Kidney Disease by Regulating the miR-196a/Wnt/β-Catenin Signaling.

Xiangnan Dong, Rui Cao, Qiang Li, Lianghong Yin.

INTRODUCTION: Long noncoding RNAs (lncRNAs) have been reported to be involved in the occurrence and development of various diseases. This study was to investigate the role of lncRNA-H19 in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) and its underlying mechanism.
METHODS: Bilateral renal pedicle ischemia-reperfusion injury (IRI) was used to establish the IRI-AKI model in C57BL/6 mice. The expression levels of lncRNA-H19, miR-196a-5p, α-SMA, collagen I, Wnt1, and β-catenin in mouse kidney tissues and fibroblasts were determined by quantitative real-time PCR and Western blotting. The degree of renal fibrosis was evaluated by hematoxylin and eosin staining. The interaction between lncRNA-H19 and miR-196a-5p was verified by bioinformatics analysis and luciferase reporter assay. Immunohistochemistry and immunofluorescence were used to evaluate the expression of α-SMA and collagen I in kidney tissues and fibroblasts of mice.
RESULTS: lncRNA-H19 is upregulated, and miR-196a-5p is downregulated in kidney tissues of IRI mice. Moreover, miR-196a-5p is a direct target of lncRNA-H19. lncRNA-H19 overexpression promotes kidney fibrosis and activates fibroblasts during AKI-CKD development, while miR-196a-5p overexpression reversed these effects in vitro. Furthermore, lncRNA-H19 overexpression significantly upregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice, while miR-196a-5p overexpression downregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice.
CONCLUSION: lncRNA-H19 induces kidney fibrosis during AKI-CKD by regulating the miR-196a-5p/Wnt/β-catenin signaling pathway.

Keywords: Acute kidney injury; Chronic kidney disease; Long noncoding RNA-H19; MiR-196a-5p; Wnt/β-catenin

DOI: https://doi.org/10.1159/000518756

Cancer Sci. 2021 Nov 23.

METTL14 suppresses growth and metastasis of renal cell carcinoma by decreasing long non-coding RNA NEAT1.

Tao Liu, Hui Wang, Zhibin Fu, Zheng Wang, Jie Wang, Xinxin Gan, Anbang Wang, Linhui Wang.

Growing evidence supports that N6-methyladenosine (m6A) modification acts as a critical regulator involved in tumorigenesis at the mRNA level. However, the role of m6A modification at the ncRNA level remains largely unknown. We found that methyltransferase-like 14 (METTL14) was significantly downregulated in renal cell carcinoma (RCC) tissues (n=580). Gain-of-function and loss-of-function experiments revealed that METTL14 attenuated the proliferation and migration ability of RCC cells in vivo and in vitro. The methylated RNA immunoprecipitation experiments identified that METTL14 decreased the expression of lncRNA nuclear enriched abundant transcript 1_1 (NEAT1_1) in an m6A-dependent manner. Mechanistically, RNA pull-down assay and RNA immunoprecipitation identified NEAT1_1 directly bound to m6A reader YTHDF2. Notably, YTHDF2 accelerated the degradation of NEAT1_1 by selectively recognizing METTL14-mediated m6A marks on NEAT1_1. Multivariate analysis suggested that METTL14 downregulation was associated with the malignant characteristics and predicted poor prognosis in RCC patients. In conclusion, our results uncover a newly identified METTL14-YTHDF2-NEAT1_1 signaling axis, which facilitates RCC growth and metastasis and provides fresh insight into RCC therapy.

Keywords: Long non-coding RNA; METTL14; Renal cell carcinoma; YTHDF2; m6A

DOI: https://doi.org/10.1111/cas.15212

Molecules. 2021 Nov 22. pii: 7040. [Epub ahead of print]26(22):

LINC02532 Contributes to Radiosensitivity in Clear Cell Renal Cell Carcinoma through the miR-654-5p/YY1 Axis.

Xiaoguang Zhou, Bowen Zeng, Yansheng Li, Haozhou Wang, Xiaodong Zhang.

BACKGROUND: Studies have shown that long non-coding RNAs (lncRNAs) play essential roles in tumor progression and can affect the response to radiotherapy, including in clear cell renal cell carcinoma (ccRCC). LINC02532 has been found to be upregulated in ccRCC. However, not much is known about this lncRNA. Hence, this study aimed to investigate the role of LINC02532 in ccRCC, especially in terms of radioresistance.
METHODS: Quantitative real-time PCR was used to detect the expression of LINC02532, miR-654-5p, and YY1 in ccRCC cells. Protein levels of YY1, cleaved PARP, and cleaved-Caspase-3 were detected by Western blotting. Cell survival fractions, viability, and apoptosis were determined by clonogenic survival assays, CCK-8 assays, and flow cytometry, respectively. The interplay among LINC02532, miR-654-5p, and YY1 was detected by chromatin immunoprecipitation and dual-luciferase reporter assays. In addition, in vivo xenograft models were established to investigate the effect of LINC02532 on ccRCC radioresistance in 10 nude mice.
RESULTS: LINC02532 was highly expressed in ccRCC cells and was upregulated in the cells after irradiation. Moreover, LINC02532 knockdown enhanced cell radiosensitivity both in vitro and in vivo. Furthermore, YY1 activated LINC02532 in ccRCC cells, and LINC02532 acted as a competing endogenous RNA that sponged miR-654-5p to regulate YY1 expression. Rescue experiments indicated that miR-654-5p overexpression or YY1 inhibition recovered ccRCC cell functions that had been previously impaired by LINC02532 overexpression.
CONCLUSIONS: Our results revealed a positive feedback loop of LINC02532/miR-654-5p/YY1 in regulating the radiosensitivity of ccRCC, suggesting that LINC02532 might be a potential target for ccRCC radiotherapy. This study could serve as a foundation for further research on the role of LINC02532 in ccRCC and other cancers.

Keywords: LINC02532; YY1; clear cell renal cell carcinoma; miR-654-5p; radioresistance

DOI: https://doi.org/10.3390/molecules26227040

J Cardiovasc Pharmacol. 2021 Nov 15.

LncRNA NEAT1 accelerates the proliferation, oxidative stress, inflammation and fibrosis and suppresses the apoptosis via miR-423-5p/GLIPR2 axis in diabetic nephropathy.

Xu Wu, Deyong Fan, Bo Chen.

ABSTRACT: Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. The aim of our study was to investigate the potential mechanism in DN progression. SV40 MES13 cells were exposed to high concentration of glucose (HG: 30 mmol/L) for 48 h to establish DN cell model in vitro. Bioinformatic software StarBase was adopted to establish long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay were performed to verify intermolecular interaction. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was overexpressed in the serum of DN patients. HG time-dependently up-regulated NEAT1 level, and HG promotes cell proliferation, oxidative stress, inflammation and fibrosis and suppressed cell apoptosis in SV40 MES13 cells partly via up-regulating NEAT1. NEAT1 functioned as a molecular sponge of miR-423-5p, and NEAT1 silencing-mediated effects were partly overturned by miR-423-5p interference in HG-induced SV40 MES13 cells. Glioma pathogenesis related-2 (GLIPR2) was a target of miR-423-5p. GLIPR2 overexpression in normal concentration of glucose (NG)-induced SV40 MES13 cells partly simulated HG-induced effects. GLIPR2 overexpression partly reversed NEAT1 interference-induced effects in HG-induced SV40 MES13 cells. LncRNA NEAT1 contributed to HG-induced DN progression via miR-423-5p/GLIPR2 axis in vitro. NEAT1/miR-423-5p/GLIPR2 axis might be potential target for DN treatment.

DOI: https://doi.org/10.1097/FJC.0000000000001177