miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy

• Published in: Molecular and cellular endocrinology Vol. 433; pp. 75 - 86
• Main Authors: Sun, Yan, Peng, Rui, Peng, Huimin, Liu, Handeng, Wen, Li, Wu, Tianhui, Yi, Hong, Li, Ailing, Zhang, Zheng
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.09.2016
• Subjects: Animals; blood glucose; Cell Line; chromatin; Diabetes Mellitus, Experimental; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Down-Regulation - physiology; excretion; gene expression regulation; glucose; Glucose - metabolism; high-throughput nucleotide sequencing; in situ hybridization; Inflammation; Inflammation - metabolism; Kidney - metabolism; Kidney Glomerulus - metabolism; kidneys; LMP7; Male; Mesangial Cells - metabolism; Mice; MicroRNAs - metabolism; MiR-451; mononuclear leukocytes; NF- κB; NF-kappa B - metabolism; patients; precipitin tests; Proteasome Endopeptidase Complex - metabolism; proteinases; quantitative polymerase chain reaction; reporter genes; Signal Transduction - physiology; transcription factor NF-kappa B; Transcription, Genetic - physiology; Western blotting; LMP2; TGF- β1; FN; Inflammation; ICAM-1; LMP7; TNF-α; MECL-1; IL-18; Diabetic nephropathy; NF- κB; MiR-451; MYD88
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2016.06.004

Activation of nuclear factor -kappa B (NF-κB) is associated with inflammation in the progression of diabetic nephropathy (DN). MiR-451 is closely linked to renal damage in DN. Large multifunctional protease 7 (LMP7), an immunoproteasome subunit, can activate NF-κB. However, it remained unclear whether miR-451 affected NF-κB-induced inflammation by regulating LMP7 in DN. In this study, deep sequencing, in situ hybridization, quantitative real-time PCR, dual-luciferase reporter gene assays, western blot and chromatin immunoprecipitation were respectively used. For the results, we found that miR-451 was markedly downregulated in the kidneys of db/db mice, PBMCs of DN patients and mesangial cells (MCs) cultured in high glucose conditions. Furthermore, miR-451 directly targeted LMP7 expression to inhibit NF-κB activity, and down-regulated transcription of proinflammatory molecules in MCs. More importantly, in the kidneys of db/db DN mice, increasing miR-451 level inhibited LMP7/NF-κB activity, and attenuated the urinary microalbumin excretion, blood glucose, and glomerular injury. In conclusion, these results provide new insights into the regulation of miR-451 via the LMP7/NF-κB central inflammatory pathway during progression of DN. [Display omitted] •miR-451 was knockdown and LMP7 was overexpression in kidneys of db/db DN mice and high glucose cultured MCs.•miR-451 directly inhibited LMP7 to decrease NF-κB-mediated inflammation in H-MC and in the kidneys of db/db DN mice.•overexpression of miR-451 attenuated glomerular damage in db/db mice.