Novel Long Noncoding RNA lnc-URIDS Delays Diabetic Wound Healing by Targeting Plod1

Abstract

Impaired wound healing is one of the main causes of diabetic foot ulcerations. However, the exact mechanism of delayed wound healing in diabetes is not fully understood. Long noncoding RNAs (lncRNAs) are widely involved in a variety of biological processes and diseases, including diabetes and its associated complications. In this study, we identified a novel lncRNA, MRAK052872, named lncRNA UpRegulated in Diabetic Skin (lnc-URIDS), which regulates wound healing in diabetes. lnc-URIDS was highly expressed in diabetic skin and dermal fibroblasts treated with advanced glycation end products (AGEs). lnc-URIDS knockdown promoted migration of dermal fibroblasts under AGEs treatment in vitro and accelerated diabetic wound healing in vivo. Mechanistically, lnc-URIDS interacts with procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1), a critical enzyme responsible for collagen cross-linking. The binding of lnc-URIDS to Plod1 results in a decreased protein stability of Plod1, which ultimately leads to the dysregulation of collagen production and deposition and delays wound healing. Collectively, this study identifies a novel lncRNA that regulates diabetic wound healing by targeting Plod1. The findings of the current study offer some insight into the potential mechanism for the delayed wound healing in diabetes and provide a potential therapeutic target for diabetic foot.

Epigenetic regulation of cellular functions in wound healing

“…31 These data support therapeutic application of MSC-derived exosomes carrying lncRNA H19 for improved diabetic fibroblast function. 30 A study by Hu et al 32 showed that lncRNA URIDS (Upregulated in Diabetic Skin) is highly expressed in diabetic skin and upregulated in dermal fibroblasts treated with advanced glycation end products (AGE). Silencing of lncRNA URIDS promoted migration of diabetic fibroblasts despite AGE treatment and accelerated wound closure in vivo.…”

“…The lncRNA URIDS regulates wound healing through interaction with PLOD1 (Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1), which results in decreased PLOD1 protein stability and deregulation of collagen production and ultimately delayed healing. 32 Another lncRNA TETILA (TET2-interacting long non-coding RNA) was found upregulated in human diabetic skin, 33 where it activates transcription of MMP-9 (Matrix Metalloprotease 9), an indicator of poor wound healing in DFUs. 34,35 Silencing of TETILA increased migration of diabetic keratinocytes even in the presence of AGE.…”

Long non‐coding RNAs in diabetic wound healing: Current research and clinical relevance

“…Lnc‐RNA MRAK052872 (named lnc‐URIDS) is dramatically increased not only in the diabetic skin, but also in the serum of type 2 DM patients with DFU, indicating its participation in wound healing of diabetes 73 …”

Emerging Roles of Long Non-Coding RNAs in Diabetic Foot Ulcers

“…Hu et al annotated and characterized a novel lncRNA, MRAK052872, which was significantly upregulated in the fibroblasts of the dermal layer in diabetic skin tissue. 105 Therefore, this lncRNA was later named URIDS (UpRegulated in Diabetic Skin). They further studied its function by knocking down the expression of URIDS and found that the migration of AGE-treated fibroblasts was significantly increased.…”