Down‐regulation of the long non‐coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR‐217–TLR4 pathway

Abstract

New Findings What is the central question of this study?What is the role of the long non‐coding RNA X‐inactive specific transcript (XIST), which is up‐regulated in injured podocytes and membranous nephropathy, in the pathogenesis of membranous nephropathy? What is the main finding and its importance?XIST was up‐regulated in kidney tissue with membranous nephropathy and in injured podocytes. Down‐regulation of XIST inhibited podocyte apoptosis. XIST negatively regulated miR‐217, and miR‐217 modulated Toll‐like receptor 4. Inhibition of XIST suppressed podocyte apoptosis induced by angiotensin II via miR‐217. Abstract Membranous nephropathy is often characterized by glomerular podocyte injury. Up‐regulation of the long non‐coding RNA (lncRNA) X‐inactive specific transcript (XIST) has been verified in membranous nephropathy and in injured podocytes. Here the role of XIST in podocyte injury and membranous nephropathy was explored. Quantitative real‐time PCR and western blot were performed to detect the expression of XIST and miR‐217, and Toll‐like receptor 4 (TLR4) protein, respectively. Podocyte apoptosis was evaluated with flow cytometry. Interaction between XIST and miR‐217 was analysed by RNA immunoprecipitation and RNA pull‐down assay. A dual luciferase reporter assay was used to examine the interplay between miR‐217 and TLR4. Up‐regulation of the lncRNA XIST and angiotensin II (Ang II) and kidney and podocyte injury were indicated in kidney tissue of patients with membranous nephropathy. Increase of XIST and apoptosis were induced by Ang II in podocytes. Down‐regulation of XIST reversed podocyte apoptosis induced by Ang II. MiR‐217 was negatively regulated by XIST. MiR‐217 controlled TLR4 by targeting its 3′‐untranslated region. XIST modulated TLR4 through miR‐217 and inhibition of XIST reduced podocyte apoptosis induced by Ang II via regulating miR‐217. Down‐regulation of XIST ameliorates podocyte apoptosis via the miR‐217–TLR4 pathway, which may improve membranous nephropathy.

RETRACTED: LSAMP-AS1 binds to microRNA-183–5p to suppress the progression of prostate cancer by up-regulating the tumor suppressor DCN

“…Subsequently, the beads were washed 3 times in wash buffer (50 mM Tris–HCl, 300 mM NaCl pH 7.4, 1 mM MgCl 2 , 0.1% Nonidet P-40) followed by RNA extraction using the Trizol reagent (Invitrogen, USA). The expression of LSAMP-AS1 and miR-183–5p was determined by reverse transcription quantitative PCR (RT-qPCR) [29].…”

Interactions Among Non-Coding RNAs in Diabetic Nephropathy

“…In hyperglycemic condition, GAS5 inhibits the regulatory action of miR-27a towards the BCL2 Interacting Protein 3 (BNIP3), thus causing an upregulation of BNIP3 expression and renal tubular epithelial cell apoptosis (Lv et al, 2019). Another lncRNA is the lncRNA XIST, in which its expression was high in patients with primary membranous nephropathy, and this high expression of lncRNA XIST was due to Ang II treatment that promotes podocyte apoptosis (Jin et al, 2019). In this study, higher expression of lncRNA XIST inhibited the miR-217 action from suppressing the TLR4 expression; thus, leads to TRL4 activation of inflammatory and apoptosis effects (Jin et al, 2019).…”

“…Another lncRNA is the lncRNA XIST, in which its expression was high in patients with primary membranous nephropathy, and this high expression of lncRNA XIST was due to Ang II treatment that promotes podocyte apoptosis (Jin et al, 2019). In this study, higher expression of lncRNA XIST inhibited the miR-217 action from suppressing the TLR4 expression; thus, leads to TRL4 activation of inflammatory and apoptosis effects (Jin et al, 2019). Interestingly, lncRNA XIST expression can be detected in the urine samples (Huang et al, 2014) thus suggesting the potential of this lncRNA as a biomarker for DN.…”

Long Non-Coding RNAs in Kidney Disease

“…The actual pathophysiological impact of this work remains to be determined. One of the longest-known lncRNAs—XIST, which is known for its role in the inactivation of the X-chromosome—has been linked to membranous nephropathy (MN) [48,55]. This lncRNA was found to be upregulated both in a mouse model of MN and in human samples [55].…”

“…This lncRNA was found to be upregulated both in a mouse model of MN and in human samples [55]. Data in cell culture pointed towards XIST exerting its proapoptotic effect on podocytes through sequestration of miR-217 and consecutive upregulation of Toll-like receptor 4 [48]. Finally, in a recent report Liao et al showed differential expression of lncRNAs in kidney biopsies of patients diagnosed with lupus nephritis (LN) [49].…”