Abstract
Background: Diabetic neuropathy is a serious complication for diabetic patients involving the nervous system. This disease is a quiet but painful condition caused by chronically high blood glucose levels. It is reported that high mobility group box 1 protein (HMGB1) participates in the development of neuropathic pain. This study aimed to explore the role of microRNA (miR)-193a in diabetic neuropathic pain through the regulation of HMGB1. Methods: A diabetic mouse model was established through the injection of streptozocin (STZ). Neuropathic pain development was shown by paw withdrawal thresholds and paw withdrawal latency. Expression levels of relative genes or miR were analyzed by qRT-PCR, while Western blot was employed to assess the protein levels. The interaction between miR-193a and HMGB1 mRNA 3′-UTR region was shown by luciferase assay. The levels of inflammation cytokines were measured by ELISA kits. Results: miR-193a expression was decreased and HMGB1 expression was upregulated in the lumbar spinal dorsal horn of STZ-induced diabetic mice. miR-193a inhibited HMGB1 expression in the lumbar spinal dorsal horn. Overexpression of miR-193a alleviated neuropathic pain in STZ-induced diabetic mice. Peripheral neuroinflammation in diabetic mice was suppressed by miR-193a overexpression. Conclusion: This research illustrates that miR-193a alleviates diabetic neuropathic pain in a mouse model through the inhibition of HMGB1 expression.
References
1.
Shenoy
AM
. Guidelines in practice: treatment of painful diabetic neuropathy
. Continuum (Minneap Minn)
. 2012
Feb
;18
(1
):192
–8
.
[PubMed]
1080-23712.
Feldman
EL
, Nave
KA
, Jensen
TS
, Bennett
DL
. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain
. Neuron
. 2017
Mar
;93
(6
):1296
–313
.
[PubMed]
0896-62733.
Nickerson
DS
. Rationale, science, and economics of surgical nerve decompression for diabetic neuropathy foot complications
. Clin Podiatr Med Surg
. 2016
Apr
;33
(2
):267
–82
.
[PubMed]
0891-84224.
Abbott
CA
, Malik
RA
, van Ross
ER
, Kulkarni
J
, Boulton
AJ
. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K
. Diabetes Care
. 2011
Oct
;34
(10
):2220
–4
.
[PubMed]
0149-59925.
Finnerup
NB
, Haroutounian
S
, Kamerman
P
, Baron
R
, Bennett
DL
, Bouhassira
D
, et al. Neuropathic pain: an updated grading system for research and clinical practice
. Pain
. 2016
Aug
;157
(8
):1599
–606
.
[PubMed]
0304-39596.
Yang
H
, Antoine
DJ
, Andersson
U
, Tracey
KJ
. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis
. J Leukoc Biol
. 2013
Jun
;93
(6
):865
–73
.
[PubMed]
0741-54007.
Andersson
U
, Tracey
KJ
. HMGB1 is a therapeutic target for sterile inflammation and infection
. Annu Rev Immunol
. 2011
;29
(1
):139
–62
.
[PubMed]
0732-05828.
Maeda
T
, Ozaki
M
, Kobayashi
Y
, Kiguchi
N
, Kishioka
S
. HMGB1 as a potential therapeutic target for neuropathic pain
. J Pharmacol Sci
. 2013
;123
(4
):301
–5
.
[PubMed]
1347-86139.
Mohr
AM
, Mott
JL
. Overview of microRNA biology
. Semin Liver Dis
. 2015
Feb
;35
(1
):3
–11
.
[PubMed]
0272-808710.
Krol
J
, Loedige
I
, Filipowicz
W
. The widespread regulation of microRNA biogenesis, function and decay
. Nat Rev Genet
. 2010
Sep
;11
(9
):597
–610
.
[PubMed]
1471-005611.
Khoo
CP
, Roubelakis
MG
, Schrader
JB
, Tsaknakis
G
, Konietzny
R
, Kessler
B
, et al. miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration
. Sci Rep
. 2017
Mar
;7
(1
):44137
.
[PubMed]
2045-232212.
Wang
SN
, Zhao
XQ
, Yu
B
, Wang
BW
. miR-193a inhibits osteogenic differentiation of bone marrow-derived stroma cell via targeting HMGB1
. Biochem Biophys Res Commun
. 2018
Sep
;503
(2
):536
–43
.
[PubMed]
0006-291X13.
Wu
H
, Zhou
C
. Long non-coding RNA UCA1 promotes lung cancer cell proliferation and migration via microRNA-193a/HMGB1 axis
. Biochem Biophys Res Commun
. 2018
Feb
;496
(2
):738
–45
.
[PubMed]
0006-291X14.
Kaur
S
, Pandhi
P
, Dutta
P
. Painful diabetic neuropathy: an update
. Ann Neurosci
. 2011
Oct
;18
(4
):168
–75
.
[PubMed]
0972-753115.
Edwards
JL
, Vincent
AM
, Cheng
HT
, Feldman
EL
. Diabetic neuropathy: mechanisms to management
. Pharmacol Ther
. 2008
Oct
;120
(1
):1
–34
.
[PubMed]
0163-725816.
Obrosova
IG
. Diabetes and the peripheral nerve
. Biochim Biophys Acta
. 2009
Oct
;1792
(10
):931
–40
.
[PubMed]
0006-300217.
Arnold
R
, Kwai
NC
, Krishnan
AV
. Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies
. Clin Neurophysiol
. 2013
Nov
;124
(11
):2079
–90
.
[PubMed]
1388-245718.
Ramirez
HA
, Liang
L
, Pastar
I
, Rosa
AM
, Stojadinovic
O
, Zwick
TG
, et al. Comparative genomic, microrna, and tissue analyses reveal subtle differences between non-diabetic and diabetic foot skin
. PLoS One
. 2015
Aug
;10
(8
):e0137133
.
[PubMed]
1932-620319.
Fan
Q
, Hu
X
, Zhang
H
, Wang
S
, Zhang
H
, You
C
, et al. Mir-193a-3p is an important tumour suppressor in lung cancer and directly targets kras
. Cell Physiol Biochem
. 2017
;44
(4
):1311
–24
.
[PubMed]
1015-898720.
Jensen
TS
, Finnerup
NB
. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms
. Lancet Neurol
. 2014
Sep
;13
(9
):924
–35
.
[PubMed]
1474-442221.
Mamoori
A
, Gopalan
V
, Lam
AK
. Role of mir-193a in cancer: complexity and factors control the pattern of its expression
. Curr Cancer Drug Targets
. 2018
;18
(7
):618
–28
.
[PubMed]
1568-009622.
Yang
D
, Chen
Q
, Yang
H
, Tracey
KJ
, Bustin
M
, Oppenheim
JJ
. High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin
. J Leukoc Biol
. 2007
Jan
;81
(1
):59
–66
.
[PubMed]
0741-540023.
Ren
PC
, Zhang
Y
, Zhang
XD
, An
LJ
, Lv
HG
, He
J
, et al. High-mobility group box 1 contributes to mechanical allodynia and spinal astrocytic activation in a mouse model of type 2 diabetes
. Brain Res Bull
. 2012
Jul
;88
(4
):332
–7
.
[PubMed]
0361-923024.
Grossi
I
, Salvi
A
, Abeni
E
, Marchina
E
, De Petro
G
. Biological function of microrna193a-3p in health and disease
. Int J Genomics
. 2017
;2017
:5913195
.
[PubMed]
2314-436X25.
Chattopadhyay
M
, Zhou
Z
, Hao
S
, Mata
M
, Fink
DJ
. Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy
. Mol Pain
. 2012
Mar
;8
:17
.
[PubMed]
1744-806926.
Im
YB
, Jee
MK
, Choi
JI
, Cho
HT
, Kwon
OH
, Kang
SK
. Molecular targeting of NOX4 for neuropathic pain after traumatic injury of the spinal cord
. Cell Death Dis
. 2012
Nov
;3
(11
):e426
.
[PubMed]
2041-488927.
Willemen
HL
, Huo
XJ
, Mao-Ying
QL
, Zijlstra
J
, Heijnen
CJ
, Kavelaars
A
. MicroRNA-124 as a novel treatment for persistent hyperalgesia
. J Neuroinflammation
. 2012
Jun
;9
(1
):143
.
[PubMed]
1742-2094© 2019 S. Karger AG, Basel
2019
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