LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose‐induced podocyte injury via its interplay with β‐catenin

Abstract

Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non‐coding RNA, broadly expressed in mammalian tissues including kidney and up‐regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. β‐catenin is a key mediator in the canonical and non‐canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)‐induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline. The decline of MALAT1 levels was accompanied with β‐catenin translocation to the nuclei and enhanced expression of serine/arginine splicing factor 1 (SRSF1), a MALAT1 RNA‐binding protein. Further we showed early interference with MALAT1 siRNA partially restored podocytes function and prohibited β‐catenin nuclear accumulation and SRSF1 overexpression. Intriguingly, we showed that β‐catenin was involved in MALAT1 transcription by binding to the promotor region of MALAT1; β‐catenin knock‐down also decreased MALAT1 levels, suggesting a novel feedback regulation between MALAT1 and β‐catenin. Notably, β‐catenin deletion had limited effects on SRSF1 expression, demonstrating β‐catenin might serve as a downstream signal of SRSF1. These findings provided evidence for a pivotal role of MALAT1 in diabetic nephropathy and high glucose‐induced podocyte damage.

LncRNA TPT1‐AS1 promotes tumorigenesis and metastasis in epithelial ovarian cancer by inducing TPT1 expression

“…Because siRNA mainly exert their gene‐silencing effects in cytoplasm, the RNA interference in nuclei does not seem as effective as in cytoplasm. However, in some studies, siRNA were utilized to silence lncRNA and mRNA expression in the nuclei, and the downstream genes and effects were efficaciously regulated . In our study, the TPT1‐AS1 depletion EOC cell lines were constructed by siRNA transfection, and were further utilized for in vitro function experiments.…”

“…However, in some studies, siRNA were utilized to silence lncRNA and mRNA expression in the nuclei, and the downstream genes and effects were efficaciously regulated. [41][42][43][44] In our study, the TPT1-AS1 depletion EOC cell lines were constructed by siRNA transfection, and were further utilized for in vitro function experiments. As the results showed, the knockdown efficiency of TPT1-AS1 was approximately 30%-40%, and the downregulation of TPT1-AS1 dramatically attenuated EOC cell proliferation, migration and invasion ability, and promoted cell adhesion ability, which are significantly opposite to the oncogenic effects of TPT1-AS1 overexpression.…”

Long noncoding RNA growth arrest‐specific transcript 5 alleviates renal fibrosis in diabetic nephropathy by downregulating matrix metalloproteinase 9 through recruitment of enhancer of zeste homolog 2

“…In recent years, lncRNAs have been identified to play a regulatory role in the pathogenesis of diabetic kidney diseases . Growing evidences have shown that a variety of lncRNAs are involved in DN . LncRNA GAS5, encodes a complicated repertoire of alternatively‐spliced lncRNA isoforms and is a host gene of numerous small nucleolar RNAs, which are processed from its introns .…”

“…9 Growing evidences have shown that a variety of lncRNAs are involved in DN. 10,11 LncRNA GAS5, encodes a complicated repertoire of alternatively-spliced lncRNA isoforms and is a host gene of numerous small nucleolar RNAs, which are processed from its introns. 12 The reduced expression of GAS5 has been reported to be associated with the occurrence of type 2 DM.…”

The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis

“…Several lines of evidence suggest that lncRNAs are involved in the pathogenesis of podocyte injury. Hu et al (7) reported that the level of the lncRNA MALAT1 was elevated in diabetic nephropathy and was involved in high glucose-induced podocyte injury via its interplay with ␤-catenin. Long et al (8) reported that Tug1 regulates mitochondrial function in podocytes by the epigenetic targeting of the transcription factor peroxisome proliferator-activated receptor ␥ coactivator 1␣.…”