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

• Published in: Experimental physiology Vol. 104; no. 2; pp. 220 - 230
• Main Authors: Jin, Ling‐wei, Pan, Min, Ye, Han‐yang, Zheng, Yu, Chen, Yan, Huang, Wen‐wen, Xu, Xiao‐yan, Zheng, Shu‐bei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-02-2019
• Subjects: Angiotensin; Angiotensin II; Apoptosis; Flow cytometry; Immunoprecipitation; Kidneys; Membranous nephropathy; miR‐217; Nephropathy; podocytes; Ribonucleic acid; RNA; TLR4; TLR4 protein; Toll-like receptors; Transcription; XIST; XIST; podocytes; TLR4; membranous nephropathy; miR-217
• ISSN: 0958-0670; 1469-445X
• DOI: 10.1113/EP087190

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.
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.