miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy.
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.
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Yan
Y
Sun
Department of Bioinformatics, Chongqing Medical University, Chongqing 400016, China.
Rui
R
Peng
Experimental Teaching Center, Chongqing Medical University, Chongqing 400016, China.
Huimin
H
Peng
Experimental Teaching Center, Chongqing Medical University, Chongqing 400016, China.
Handeng
H
Liu
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Li
L
Wen
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Tianhui
T
Wu
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Hong
H
Yi
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
Ailing
A
Li
Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China. Electronic address: zhangzheng92@163.com.
Zheng
Z
Zhang
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D016328:NF-kappa B; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
Diabetic nephropathy; Inflammation; LMP7; MiR-451; NF- κB