MicroRNA‐7a‐5p ameliorates diabetic peripheral neuropathy by regulating VDAC1/JNK/c‐JUN pathway

• Published in: Diabetic medicine Vol. 40; no. 1; pp. e14890 - n/a
• Main Authors: Jiao, Yang, Zhang, Yue‐Hua, Wang, Chun‐Yan, Yu, Yang, Li, Yi‐Ze, Cui, Wei, Li, Qing, Yu, Yong‐Hao
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2023
• Subjects: Animals; Apoptosis; Calcium (intracellular); Calcium (mitochondrial); Calcium - adverse effects; Calcium - metabolism; Cell growth; Cell proliferation; Cellular stress response; Cholecystokinin; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental; Diabetic Neuropathies - genetics; Diabetic Neuropathies - pathology; diabetic peripheral neuropathy; Electromyography; Flow cytometry; Intracellular signalling; JNK/c‐JUN pathway; Kinases; Membrane potential; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; MiR‐7a‐5p; Mitochondria; mitochondrial dysfunction; Nerve conduction; Oxidative stress; Peripheral neuropathy; Rats; Reporter gene; RSC96 cells; Signal transduction; Streptozocin; VDAC1; Voltage-Dependent Anion Channel 1; Western blotting; diabetic peripheral neuropathy; JNK/c-JUN pathway; MiR-7a-5p; VDAC1; mitochondrial dysfunction; RSC96 cells
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/dme.14890

Aims The pathogenesis of diabetic peripheral neuropathy (DPN) is complex, and its treatment is extremely challenging. MicroRNA‐7a‐5p (miR‐7a‐5p) has been widely reported to alleviate apoptosis and oxidative stress in various diseases. This study aimed to investigate the mechanism of miR‐7a‐5p in DPN. Methods DPN cell model was constructed with high‐glucose–induced RSC96 cells. Cell apoptosis and viability were detected by flow cytometry analysis and cell counting kit‐8 (CCK‐8) assay respectively. The apoptosis and Jun N‐terminal kinase (JNK)/c‐JUN signalling pathway‐related proteins expression were detected by Western blotting. The intracellular calcium content and oxidative stress levels were detected by flow cytometry and reagent kits. Mitochondrial membrane potential was evaluated by tetrechloro‐tetraethylbenzimidazol carbocyanine iodide (JC‐1) staining. The targeting relationship between miR‐7a‐5p and voltage‐dependent anion‐selective channel protein 1 (VDAC1) was determined by RNA pull‐down assay and dual‐luciferase reporter gene assay. The streptozotocin (STZ) rat model was constructed to simulate DPN in vivo. The paw withdrawal mechanical threshold (PTW) was measured by Frey capillary line, and the motor nerve conduction velocity (MNCV) was measured by electromyography. Results MiR‐7a‐5p expression was decreased, while VDAC1 expression was increased in HG‐induced RSC96 cells and STZ rats. In HG‐induced RSC96 cells, miR‐7a‐5p overexpression promoted cell proliferation, inhibited apoptosis, down‐regulated calcium release, improved mitochondrial membrane potential and repressed oxidative stress response. MiR‐7a‐5p negatively regulated VDAC1 expression. VDAC1 knockdown improved cell proliferation activity, suppressed cell apoptosis and mitochondrial dysfunction by inhibiting JNK/c‐JUN pathway activation. MiR‐7a‐5p overexpression raised PTW, restored MNCV and reduced oxidative stress levels and nerve cell apoptosis in STZ rats. Conclusion MiR‐7a‐5p overexpression ameliorated mitochondrial dysfunction and inhibited apoptosis in DPN by regulating VDAC1/JNK/c‐JUN pathway.