circMTND5 Participates in Renal Mitochondrial Injury and Fibrosis by Sponging MIR6812 in Lupus Nephritis

Abstract

Recent studies have focused on nuclear-encoded circular RNAs (circRNAs) in kidney diseases, but little is known about mitochondrial circRNAs. Differentially expressed circRNAs were analyzed by RNA deep sequencing from lupus nephritis (LN) biopsies and normal human kidneys. In LN renal biopsies, the most downregulated circRNA was circMTND5, which is encoded in the mitochondrial genome. We quantitated circMTND5 by qPCR and localized by fluorescence in situ hybridization (FISH). Mitochondrial abnormalities were identified by electron microscopy. The expression of mitochondrial genes was decreased, and the expression of profibrotic genes was increased on qPCR and immunostaining. RNA binding sites for MIR6812 and circMTND5 were predicted. MIR6812 expression was increased by FISH and qPCR. In HK-2 cells and its mitochondrial fraction, the role of circMTND5 sponging MIR6812 was assessed by their colocalization in mitochondria on FISH, RNA immunoprecipitation, and RNA pulldown coupled with luciferase reporter assay. circMTND5 knockdown upregulated MIR6812, decreased mitochondrial functional gene expression, and increased profibrotic gene expression. Overexpression of circMTND5 reversed these effects in hTGF-β stimulated HK-2 cells. Similar effects were observed in HK-2 cells with overexpression and with knockdown of MIR6812. We conclude that circMTND5 alleviates renal mitochondrial injury and kidney fibrosis by sponging MIR6812 in LN.

Identifying key genes related to the peritubular capillary rarefaction in renal interstitial fibrosis by bioinformatics

“…For example, HIF-1α could bind to introns and exons except for promoters discovered in this study, indicating if there were novel epigenomic modi cations that may be causes of gene expression pro les difference. Second, similar to data shown in this research, several non-coding RNAs (ncRNAs) have been received much attention in brosis 34,35 , thus deserve further investigation into the ncRNA-mediated regulatory mechanisms. Third, as has been reported recently, HIF-2α frequently overexpresses in chronic hypoxia, which inversely regulates the bronectin expression in TECs, indicating that HIF-2α activation in CKD may protect from persistent hypoxia-induced renal damage and may be the future direction for treatment of CKD 36,37 .…”

The Roles of CircRNAs in Mitochondria

“…Another circRNA encoded by mitochondrial ND5 gene is circMTND5 (chrM: 14068-14413+) 112 . CircMTND5 sponge MIR6812 and colocalize in mitochondria, alleviating renal mitochondrial injury and kidney fibrosis 112 (Figure 2 ).…”

“…Another circRNA encoded by mitochondrial ND5 gene is circMTND5 (chrM: 14068-14413+) 112 . CircMTND5 sponge MIR6812 and colocalize in mitochondria, alleviating renal mitochondrial injury and kidney fibrosis 112 (Figure 2 ). McPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1) is highly expressed in liver tumour-initiating cells (TICs).…”

Human mtDNA-Encoded Long ncRNAs: Knotty Molecules and Complex Functions

“…This constitutes an excellent example of how circular RNAs, synthesised and localised to mitochondria, can synergistically modulate mitochondrial metabolism and inflammatory response in pathological conditions. Recently, RNA deep sequencing from lupus nephritis (LN) biopsies and normal human kidneys has allowed us to identify a novel mitochondrial-encoded circular RNA, named circMTND5 [140]. This mitochondria-localised lncRNA ameliorates the clinical phenotype by sponging the miRNA MIR6812, which aggravates mitochondrial injury and renal fibrosis in LN patients.…”