Author:
Guo Yuqing,Zeng Jingyang,Zhuang Yuanzhao,Jiang Changcheng,Xie Wenqin
Abstract
AbstractDiabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.
Publisher
Springer Science and Business Media LLC
Reference29 articles.
1. Cloete, L. Diabetes mellitus: an overview of the types, symptoms, complications and management. Nurs. Stand 37(1), 61–66 (2022).
2. Yang, K. et al. Progress in the treatment of diabetic peripheral neuropathy. Biomed. Pharmacother. 148, 112717 (2022).
3. Jeyam, A. et al. Diabetic neuropathy is a substantial burden in people with type 1 diabetes and is strongly associated with socioeconomic disadvantage: a population-representative study from Scotland. Diabetes Care 43(4), 734–742 (2020).
4. Li, G. Z. et al. CaMKII and Ca(V)3.2 T-type calcium channel mediate Connexin-43-dependent inflammation by activating astrocytes in vincristine-induced neuropathic pain. Cell Biol. Toxicol. 39(3), 679–702 (2023).
5. Kasimu, A. et al. miR-125a-5p in astrocytes attenuates peripheral neuropathy in type 2 diabetic mice through targeting TRAF6. Endocrinol. Diabetes Nutr. (Engl Ed) 69(1), 43–51 (2022).