bims-lorfki 2021-02-14 papers

Issue of 2021‒02‒14
five papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Cell Death Discov. 2020 Apr 02. 6(1): 19

LncRNA GAS5 promotes apoptosis as a competing endogenous RNA for miR-21 via thrombospondin 1 in ischemic AKI.

Xuemei Geng, Nana Song, Shuan Zhao, Jiarui Xu, Yong Liu, Yi Fang, Mingyu Liang, Xialian Xu, Xiaoqiang Ding.

Mounting evidence has indicated that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) played important roles in renal ischemia/reperfusion (I/R) injury. However, the involvement of lncRNA growth arrest specific 5 (GAS5) in acute kidney injury (AKI) remained largely unexplored. This study aimed to determine possible mechanisms of GAS5 in the renal I/R process. We found that GAS5, noticeably upregulated by renal I/R injury, was further suppressed by delayed IPC while knockdown of miR-21 in vivo before IPC could significantly increased the GAS5 levels. Concurrently, TSP-1 was negatively regulated by miR-21 in vivo and vitro. Additionally, Reciprocal repression of GAS5 and miR-21 was identified. Knockdown of miR-21 in H6R0.5 treated HK-2 cells promoted apoptosis. Co-transfection of miR-21 mimic and pcDNA-GAS5 or pcDNA-Vector were performed, results of which showed that inhibition of miR-21 on TSP-1 could be rescued by overexpression of GAS5. This study suggested that GAS5 facilitated apoptosis by competitively sponging miR-21, which negatively regulated TSP-1 in renal I/R injury. This novel regulatory axis could act as a therapeutic target for AKI in the future.

DOI: https://doi.org/10.1038/s41420-020-0253-8

Cell Death Discov. 2020 Jul 03. 6(1): 55

FBXO45 is a potential therapeutic target for cancer therapy.

Min Lin, Zhi-Wei Wang, Xueqiong Zhu.

FBXO protein 45 (FBXO45), a substrate-recognition subunit of E3 ligases, has been characterised to have pivotal roles in many human diseases, including nervous system diseases, inflammatory diseases and human malignancies. In this article, we describe the expression of FBXO45 in several types of human tumour specimens and highlight the downstream substrates of FBXO45. Moreover, the biological functions of FBXO45 in the regulation of proliferation, apoptosis, the cell cycle and metastasis are mentioned. Furthermore, we describe that the expression level of FBXO45 is regulated by several upstream factors such as miR-27a, Hey1, m6A and the lncRNA RP11. As FBXO45 has a critical role in tumorigenesis and progression, FBXO45 might be a novel therapeutic target for cancer treatment.

DOI: https://doi.org/10.1038/s41420-020-0291-2

Front Pharmacol. 2020 ;11 583528

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease.

Yue-Yu Gu, Fu-Hua Lu, Xiao-Ru Huang, Lei Zhang, Wei Mao, Xue-Qing Yu, Xu-Sheng Liu, Hui-Yao Lan.

Diabetic kidney disease (DKD) is the most common diabetic complication and is a leading cause of end-stage kidney disease. Increasing evidence shows that DKD is regulated not only by many classical signaling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation, and non-coding RNA (ncRNAs). In this review, we focus on our current understanding of the role and mechanisms of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathogenesis of DKD. Of them, the regulatory role of TGF-β/Smad3-dependent miRNAs and lncRNAs in DKD is highlighted. Importantly, miRNAs and lncRNAs as biomarkers and therapeutic targets for DKD are also described, and the perspective of ncRNAs as a novel therapeutic approach for combating diabetic nephropathy is also discussed.

Keywords: TGF-β; biomarker; diabetic kidney disease; fibrosis; inflammation; long non-coding RNAs; micro RNAs; therapeutic target

DOI: https://doi.org/10.3389/fphar.2020.583528

Biosci Rep. 2021 Feb 26. pii: BSR20204099. [Epub ahead of print]41(2):

SNHG15 knockdown inhibits diabetic nephropathy progression in pediatric patients by regulating the miR-141/ICAM-1 axis in vitro.

Jiewei Liu, Dongliang Cai, Ying Wang, Yanhong Zou, Tana Zhao.

Long non-coding RNAs (lncRNAs) are confirmed to be involved in modulating diabetic nephropathy (DN). The present study is aimed to explore the regulatory mechanism of lncRNA small nucleolar RNA host gene 15 (SNHG15) on pediatric DN. Human glomerular mesangial cells (HGMCs) were exposed to high glucose (HG) to produce an in vitro model. The results showed that SNHG15 was remarkably up-regulated in pediatric DN tissues and HG-induced HGMCs. Functional experiments indicated that both silencing of SNHG15 and overexpression of miR-141 elevated the cell viability, and suppressed the inflammation in HG-induced HGMCs. SNHG15 was identified to be a lncRNA that could bind to miR-141, and ICAM-1 was a downstream target gene of miR-141. Both the low expression of miR-141 and high expression of ICAM-1 reversed the inhibiting effect of SNHG15 knockdown on inflammatory response, and the promoting effect on cell viability. To conclude, our study revealed that silencing of SNHG15 ameliorated the malignant behaviors of pediatric DN via modulating the miR-141/ICAM-1 axis in vitro.

Keywords: ICAM-1; diabetic nephropathy; high-glucose; lncRNA SNHG15; miR-141

DOI: https://doi.org/10.1042/BSR20204099

Mol Med Rep. 2021 Apr;pii: 271. [Epub ahead of print]23(4):

lncRNA PVT1 modulates NLRP3‑mediated pyroptosis in septic acute kidney injury by targeting miR‑20a‑5p.

Long-Tian Deng, Qian-Lu Wang, Can Yu, Min Gao.

Acute kidney injury (AKI) is the most common complication of sepsis. The current incidence of sepsis is high (0.3% of total population) worldwide, and septic AKI may cause death in patients. Long non‑coding (lnc)RNAs serve important roles in the pathogenesis of AKI. Therefore, the present study investigated the mechanism underlying lncRNA plasmacytoma variant translocation 1 (PVT1)‑mediated regulation of pyroptosis in septic AKI. Septic kidney injury was induced in mice using the caecal ligation and puncture method, and lipopolysaccharide (LPS)‑induced HK‑2 cell models were also established. Haematoxylin‑eosin staining was performed to assess pathological alterations of kidney tissues in the mice. The levels of IL‑1β, IL‑18 and lactate dehydrogenase were determined by conducting ELISAs. Reverse transcription‑quantitative PCR was used to detect the expression levels of PVT1 and microRNA (miR)‑20a‑5p. To assess pyroptosis, the protein expression levels of nucleotide‑binding oligomerization domain‑like receptor protein 3 (NLRP3), IL‑1β, IL‑18, apoptosis‑associated speck‑like protein containing a CARD and cleaved caspase‑1 were measured via western blotting. Flow cytometry was performed to assess the rate of cell pyroptosis. Dual luciferase reporter assays were used to assess the binding relationships of PVT1/miR‑20a‑5p and miR‑20a‑5p/NLRP3. PVT1 expression was significantly increased, whereas miR‑20a‑5p expression was significantly decreased in sepsis model mice and LPS‑induced HK‑2 cells compared with sham mice and control HK‑2 cells, respectively. PVT1 knockdown significantly suppressed cell pyroptosis and downregulated the expression of inflammatory factors in LPS‑induced HK‑2 cells. The results also indicated that PVT1 served as a sponge of miR‑20a‑5p, and miR‑20a‑5p directly targeted NLRP3. miR‑20a‑5p knockdown significantly promoted LPS‑induced cell pyroptosis. Moreover, PVT1 knockdown inhibited LPS‑induced cell pyroptosis by targeting the miR‑20a‑5p/NLRP3 signalling pathway. The results of the present study suggested that PVT1 modulated NLRP3‑mediated pyroptosis in septic AKI by targeting miR‑20a‑5p, which might suggest significant potential therapeutic targets for septic AKI.

DOI: https://doi.org/10.3892/mmr.2021.11910