Long Non-coding RNA XIST Attenuates Diabetic Peripheral Neuropathy by Inducing Autophagy Through MicroRNA-30d-5p/sirtuin1 Axis

Abstract

Diabetic peripheral neuropathy (DPN) is a prevalent diabetes mellitus (Feldman et al., 2017) complication and the primary reason for amputation. Meanwhile, long non-coding RNAs (lncRNAs) are a type of regulatory non-coding RNAs (ncRNAs) that broadly participate in DPN development. However, the correlation of lncRNA X-inactive specific transcript (XIST) with DPN remains unclear. In this study, we were interested in the role of XIST in the modulation of DPN progression. Significantly, our data showed that the expression of XIST and sirtuin1 (SIRT1) was inhibited, and the expression of microRNA-30d-5p (miR-30d-5p) was enhanced in the trigeminal sensory neurons of the diabetic mice compared with the normal mice. The levels of LC3II and Beclin-1 were inhibited in the diabetic mice. The treatment of high glucose (HG) reduced the XIST expression in Schwann cells. The apoptosis of Schwann cells was enhanced in the HG-treated cells, but the overexpression of XIST could block the effect in the cells. Moreover, the levels of LC3II and Beclin-1 were reduced in the HG-treated Schwann cells, while the overexpression of XIST was able to reverse this effect. The HG treatment promoted the production of oxidative stress, while the XIST overexpression could attenuate this result in the Schwann cells. Mechanically, XIST was able to sponge miR-30d-5p and miR-30d-5p-targeted SIRT1 in the Schwann cells. MiR-30d-5p inhibited autophagy and promoted oxidative stress in the HG-treated Schwann cells, and SIRT1 presented a reversed effect. MiR-30d-5p mimic or SIRT1 depletion could reverse XIST overexpression-mediated apoptosis and autophagy of the Schwann cells. Thus, we concluded that XIST attenuated DPN by inducing autophagy through miR-30d-5p/SIRT1 axis. XIST and miR-30d-5p may be applied as the potential targets for DPN therapy.

Research progress on the relationship between autophagy and chronic complications of diabetes

“…Enhanced miR-30d-5p in trigeminal sensory neurons of diabetic mice inhibited the levels of autophagy markers LC3II and Beclin-1. In the high glucose state, upregulation of X-inactive specific transcript of lncRNA induced autophagy which was inhibited by MiR-30d-5p thereby dealing with oxidative stress in Schwann cells and attenuating DPN ( Liu et al, 2021 ). In DPN, HDAC1 inhibited the expression of autophagy markers LC3-II/LC3-I and P62 when high glucose treated Schwann cell 96 thereby suppressing autophagy ( Du et al, 2019 ).…”

Interplay between exosomes and autophagy machinery in pain management: State of the art

“…Moreover, they highlighted that PI3K/AKT/autophagy axis has a pivotal role in retrieving CEP-induced IDD ( Zhang et al, 2021 ). In parallel with these findings, it has also been proved that autophagy can mitigate the MMPs activity and inflammatory responses to prevent NPCs matrix degradation ( Liu et al, 2021 ). In detail, autophagy-activated NPCs-derived Exo (NPCs-Exo) could recover IDD at least partly by exosomal miR-27 recruitment and targeting MMP-13 ( Liu et al, 2021 ).…”

“…In parallel with these findings, it has also been proved that autophagy can mitigate the MMPs activity and inflammatory responses to prevent NPCs matrix degradation ( Liu et al, 2021 ). In detail, autophagy-activated NPCs-derived Exo (NPCs-Exo) could recover IDD at least partly by exosomal miR-27 recruitment and targeting MMP-13 ( Liu et al, 2021 ). Long non-coding RNAs (lncRNAs) belong to regulatory ncRNAs that mainly participate in DPN development.…”

Danhong injection represses diabetic retinopathy and nephropathy advancement in diabetic mice by upregulating microRNA-30d-5p and targeting JAK1

“…Recently, the incidence of diabetes in China is elevated versus that in the US and the UK [ 2 ]. Diabetes is often accompanied by various complications, such as diabetic nephropathy [ 3 ], Cardiac dysfunction [ 4 ], retinopathy, Diabetic peripheral neuropathy [ 5 ] and so on. Diabetic nephropathy (DN) has been recognized as the most common and serious chronic complication of diabetes for a long time, accounting for about one-third of patients with diabetes [ 6 ].…”