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MicroRNA miR-145-5p Inhibits Cutaneous Wound Healing by Targeting PDGFD in Diabetic Foot Ulcer

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Abstract

Diabetic foot ulcer (DFU) is one major, common and serious chronic complication of diabetes mellitus, which is characterized by high incidence, high risk, high burden, and high treatment difficulty and is a leading cause of disability and death in patients with diabetes. Long-term hyperglycemia can result in cellular dysfunction of fibroblasts, which play pivotal roles in wound healing. MicroRNAs (miRNAs) were reported to mediate the pathological processes of multiple diseases, including diabetic wound healing. This research aimed to investigate the functional role of miR-145-5p in high-glucose (HG)-exposed fibroblasts and in DFU mouse models. Human foreskin fibroblast cells (HFF-1) were stimulated by HG to induce cell injury. MiR-145-5p level in HG-stimulated HFF-1 cells was detected via RT-qPCR. The binding between miR-145-5p and PDGFD was validated by Luciferase reporter assay. The effects of the miR-145-5p/PDGFD axis on the viability, migration, and apoptosis of HG-exposed HFF-1 cells were determined by CCK-8, wound healing, and flow cytometry assays. DFU mouse models were subcutaneously injected at the wound edges with miR-145-5p inhibitor/mimics. Images of the wounds were captured on day 0 and 8 post-injection, and wound samples were collected after mice were sacrificed for histological analysis by H&E staining. HG decreased cell viability and increased miR-145-5p expression in HFF-1 cells in a dose- and time-dependent manner. MiR-145-5p downregulation promoted cell viability and migration and inhibited cell apoptosis of HG-stimulated HFF-1 cells, while miR-145-5p overexpression exerted an opposite effect on cell viability, migration, and apoptosis. PDGFD was a direct target gene of miR-145-5p, whose silencing reversed the influence of miR-145-5p downregulation on HG-induced cellular dysfunction of HFF-1 cells. Additionally, downregulating miR-145-5p facilitated while overexpressing miR-145-5p inhibited wound healing in DFU mouse models. MiR-145-5p level was negatively associated with PDGFD level in wound tissue samples of DFU mouse models. MiR-145-5p inhibition improves wound healing in DFU through upregulating PDGFD expression.

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Funding

This work was supported by the National Natural Science Foundation of China (81960875), the Natural Science Foundation of Guangxi (2023GXNSFDA026008), Medical and Health Appropriate Technology Development and Promotion Application Project of Guangxi (S2022134), the Natural Science Research Project of Anhui Colleges and Universities (KJ2021A0696, 2022AH051456), and 512 Talent Cultivation Plan of Bengbu Medical College (by51202204).

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Authors and Affiliations

  1. Jinan University, Guangzhou, 510632, China

    Chun Wang & Biaoliang Wu

  2. Department of General Medicine, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, 233040, China

    Chun Wang

  3. Department of Pathophysiology, Bengbu Medical College, Bengbu, 233030, China

    Li Huang

  4. Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, 233040, China

    Juan Li & Dan Liu

  5. Department of Endocrinology, The Affiliated Hospital of Youjiang Medical University for Nationalities, No.18 Zhongshan Second Road, Youjiang District, Baise City, 533000, Guangxi, China

    Biaoliang Wu

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  1. Chun Wang
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  3. Juan Li
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Contributions

Chun Wang was the main designer of this study. Chun Wang, Li Huang, Juan Li, and Biaoliang Wu performed the experiments and analyzed the data. Chun Wang, Dan Liu, and Biaoliang Wu drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Biaoliang Wu.

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Wang, C., Huang, L., Li, J. et al. MicroRNA miR-145-5p Inhibits Cutaneous Wound Healing by Targeting PDGFD in Diabetic Foot Ulcer. Biochem Genet (2023). https://doi.org/10.1007/s10528-023-10551-1

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