An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy

Abstract

It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-β1 (TGF- β1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop−/− mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.

Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy

“…Among these miRNAs and also decreased miRNAs identified by small RNA sequencing in glomeruli from STZ diabetic mice22, we confirmed that miR-25 and miR-93 expressions were significantly downregulated in TGF-β treated mouse mesangial cells (MMCs), but the expression of only miR-25 was consistently and significantly decreased even in HG-treated MMCs relative to control. Since we previously showed that let-7 family (lin28-mediated)35 and miR-130b44 were downregulated under diabetic conditions by mechanisms not involving p-MeCP2, we focused on miR-25 in this study.…”

“…It is therefore important to examine the molecular mechanisms underlying the mis-regulated expression of key miRNAs associated with DN. Some reports have shown that miRNAs can be regulated by transcriptional mechanisms, including transcription of their host long non-coding RNA, and the role of chromatin histone acetylation of the miRNA promoter has also been demonstrated151819202122. However, it is not known whether diabetic conditions can alter miRNA levels by dysregulation of miRNA processing steps.…”

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes

“…16 To date, only few lncRNAs have been shown to be associated with the unfolded protein response (UPR). [22][23][24] Kato et al 22 recently demonstrated that lnc-MGC, which is induced by ER stress, is upregulated in a mouse model of diabetic nephropathy. In addition, some studies have shown that lncRNAs influence the UPR.…”

Noncoding RNA and epigenetic gene regulation in renal diseases

“…A recent study identified a lncRNA, lnc-MGC, that hosts a megacluster of miRNAs (miR-379–3072) and is differentially upregulated in diabetic kidneys via the endoplasmic reticulum (ER)-stress response pathway [86]. LNA-mediated silencing of lnc-MGC resulted in reduced levels of the host lncRNA as well as the associated miRNA cluster, leading to attenuation of profibrotic gene expression, ECM deposition, and hypertrophy.…”