Upregulation of microRNA‐424 relieved diabetic nephropathy by targeting Rictor through mTOR Complex2/Protein Kinase B signaling

• Published in: Journal of cellular physiology 2019-07, Vol.234 (7), p.11646-11653
• Main Authors: Wang, Guofeng, Yan, Yongxin, Xu, Ning, Hui, Yuan, Yin, Dong
• Format: Article
• Language: English
• Subjects: Akt; AKT protein; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Base Sequence; BAX protein; Blood; Blood Glucose - metabolism; Body weight; Caspase; Creatinine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Diabetic Nephropathies - blood; Diabetic Nephropathies - genetics; Diabetic Nephropathies - physiopathology; Diabetic nephropathy; diabetic nephropathy (DN); Disease Models, Animal; DNA nucleotidylexotransferase; Down-Regulation - drug effects; Down-Regulation - genetics; Glucose; Glucose - toxicity; Humans; Kidney Function Tests; Kidneys; Kinases; Lesions; Male; mammalian target of rapamycin (mTOR); Mechanistic Target of Rapamycin Complex 2 - metabolism; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; microRNA‐424 (miRNA‐424); miRNA; Nephropathy; Polymerase chain reaction; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Rapamycin-Insensitive Companion of mTOR Protein - metabolism; Rats, Sprague-Dawley; Ribonucleic acid; Rictor; RNA; Signal Transduction - drug effects; Signaling; Signs and symptoms; Staining; TOR protein; Up-regulation; Up-Regulation - drug effects; Up-Regulation - genetics; Urea; Urine
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27822

Objective To investigate the role of miR‐424 in diabetic nephropathy (DN) and its relationship with Rictor in mammalian target of rapamycin (mTOR) C2/Akt signaling. Methods The western blot analysis and real‐time polymerase chain reaction were used to determine the differential expression of Rictor, mTOR, and miR‐424 in DN rats. The upregulation of miR‐424 was achieved by caudal vein injection of miR‐424 mimics. The renal lesion was evaluated by hematoxylin‐eosin staining (H&E) and periodic acid schiff staining. The dual‐luciferase reporter assay was conducted to determine the binding target of miR‐424. The effect of miR‐424 upregulation on apoptosis was detected by the terminal deoxynucleotidyl transferase‐mediated 2‐Deoxyuridine‐5‐Triphosphate (dUTP) nick‐end labeling assay and western blot analysis. Results A significantly lower expression of miR‐424 and a significantly higher expression of Rictor and mTOR were found in renal tissues of DN rats. The upregulation of miR‐424 improved renal lesion and DN symptoms of blood glucose level, urine protein level, body weight, creatinine level, blood urea nitrogen, and KW/BW ratio. The upregulation of miR‐424 could significantly reduce apoptosis rates of tissue cells by decreasing the expression levels of caspase‐3 and Bax as well as increasing the level of Bcl‐2. Furthermore, Rictor was the direct target for miR‐424, and upregulation of miR‐424 inhibited Rictor through Akt signaling in renal tissue of DN rats and high‐glucose‐treated human glomerular mesangial cells. Conclusion miR‐424 contributes to alleviating the symptoms in DN rat models by targeting Rictor through mTORC2/Akt signaling. miR‐424 contributes to alleviating the symptoms in DN rat models by targeting Rictor through mTORC2/Akt signaling.