bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2021‒09‒05
three papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. Cancer Lett. 2021 Aug 27. pii: S0304-3835(21)00425-0. [Epub ahead of print]
      Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor β (ERβ) mRNA. Subsequently, the increased ERβ expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERβ/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERβ expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression.
    Keywords:  Estrogen receptor β; Long noncoding RNA; Renal cell carcinoma; Sunitinib; Vasculogenic mimicry
  2. Autoimmunity. 2021 Sep 03. 1-8
      BACKGROUND AND OBJECTIVE: Membranous nephropathy (MN) is an autoimmune disease. The up-regulation of the long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (Neat1) has been found in MN but the mechanism is still unclear. Here, we explored the effect and the underlying mechanism of lncRNA Neat1 on the apoptosis of renal tubular epithelial cells in MN.METHODS: Albumin-stimulated E11 podocytes and proximal tubular epithelial cells in vitro and the cationic-bovine serum albumin-induced MN mouse model in vivo were established. The expression of Neat1 in E11 podocytes, renal tubular epithelial cells, and renal tubules and the mRNA expression of BH3-only (the Bcl-2 homology 3-only) proteins were determined by quantitative reverse transcription-polymerase chain reaction. Levels of Cleaved Caspase 3, 6, 7, and Noxa were examined by western blotting. The number of apoptotic cells was detected by flow cytometry. Cellular proliferation was determined by 5-Ethynyl-2'-deoxyuridine and Cell Counting Kit-8 assay. Interactions between BH3-only protein Noxa and Bcl-2 as well as Bcl-xL were evaluated with co-immunoprecipitation.
    RESULTS: The expression of lncRNA Neat1 was unchanged in albumin-stimulated E11 podocytes, but it was up-regulated in albumin-stimulated renal tubular epithelial cells and MN renal tubule tissues and there was a time-dependent increase in vivo. In the albumin-stimulated proximal tubular epithelial cells, overexpression of Neat1 could increase apoptosis and decrease proliferation. In turn, interference with Neat1 reduced apoptosis and increased proliferation accordingly. The mRNA expression levels of BH3-only proteins (Bad, Bim, Bid, Puma, Noxa) were detected with qRT-PCR, the results indicated that after overexpression of Neat1, mRNA and protein levels of Noxa were significantly increased, and the interference with BH3-only protein Noxa alleviated apoptosis of renal tubular epithelial cells in vitro.
    CONCLUSION: In our study, we proved that lncRNA Neat1 promoted the development of MN by inducing apoptosis and this effect may be exerted by inhibiting the anti-apoptotic protein activity mediated by Noxa.
    Keywords:  BH3-only protein; apoptosis; lncRNA Neat1; membranous nephropathy
  3. Mol Immunol. 2021 Aug 27. pii: S0161-5890(21)00219-4. [Epub ahead of print]139 87-96
      BACKGROUND: Kidney damage often develops into renal fibrosis. Apoptosis and inflammatory response are the main factors driving the process of renal fibrosis. Here we showed that lncRNA XIST/ miR-19b / SOX6 signal axis regulated apoptosis and inflammation of renal fibrosis.METHODS: HK-2 cells were treated with TGF-β1 to construct cell fibrosis model, and UUO surgery was performed to construct mouse renal fibrosis model. The expression of XIST, miR-19b and SOX6 were examined by qPCR. And levels of fibrosis-related proteins were detected by western blotting. Levels of IL-1β and TNF-α were assessed by qPCR and ELISA, respectively. Renal pathology and fibrosis were evaluated by HE and Masson staining. Flow cytometry and TUNEL staining were employed to evaluate cell apoptosis in cell fibrosis model and mouse renal fibrosis model, respectively. Besides, dual luciferase reporter assay was employed to verify whether XIST had a binding site to miR-19b, and whether miR-19b had a binding site to SOX6.
    RESULTS: Here we showed that XIST and SOX6 were upregulated in both HK-2 cells treatment of TGF-β1 and kidneys of UUO mice, while miR-19b was downregulated. Dual luciferase reporter assay displayed that XIST directly bound to miR-19b, and SOX6 was the target of miR-19b. Knockdown of XIST inhibited apoptosis, inflammation and fibrosis in HK-2 cells treatment of TGF-β1 via miR-19b-mediated downregulation of SOX6, while inhibition of miR-19b reversed the effect. Similarly, knockdown of XIST in vivo inhibited apoptosis, inflammation and fibrosis in kidneys of UUO mice via miR-19b-mediated downregulation of SOX6.
    DISCUSSION: These results provided evidence that knockdown of XIST inhibited apoptosis and inflammation of renal fibrosis via miR-19b-mediated downregulation of SOX6.
    Keywords:  Apoptosis; Inflammation; LncRNA XIST; Renal fibrosis; SOX6; miR-19b