Background: Glomerular endothelial cell damage plays an important role in the occurrence and development of diabetic nephropathy (DN). Objectives: This study aimed to clarify the role of XCL1 in DN-mediated glomerular endothelial cell apoptosis and whether the function was related to the activation of the p53/nuclear factor-kappa B (NF-κB) signaling pathway. Methods: Candidate biomarkers were identified by least absolute shrinkage and selection operator (LASSO) regression model analysis. The area under the receiver operating characteristic curve value was calculated and used to evaluate the discriminating ability. Cell viability, apoptosis, and interleukin-1β and tumor necrosis factor-α expression at messenger RNA and protein levels were detected by using the Cell Counting Kit-8, flow cytometry, ELISA, real-time polymerase chain reaction, and Western blotting assays. In vivo studies were conducted in the DN mice. Results: The LASSO regression model displayed good discriminating performance, with a C-index of 0.803 and good calibration, and high XCL1 expression was identified as the predicting factor for DN in diabetes mellitus patients. XCL1 expression was upregulated in glomeruli of db/db mice, which was closely related to the expression of its receptor (XCR1). XCL1 overexpression played an important role in the apoptosis and inflammatory response of high glucose (HG)-treated human renal glomerular endothelial cells. Meanwhile, the expression of p53 and the levels of inflammatory cytokines were upregulated upon XCL1 overexpression. p53 silencing with its inhibitor blocked the apoptotic response and inflammatory response in XCL1-overexpressed cells exposed to HG. Besides, the XCL1 overexpression-induced downregulation of NF-κB was reversed by pifithrin-α pretreatment. Conclusions: Our findings in this work provided the mechanistic insights into the effects of XCL1 on the modulation of DN development, illustrating that XCL1 might serve as an essential prognostic indicator and therapeutic target for DN progression.

1.
Xu
J
,
Xiang
P
,
Liu
L
,
Sun
J
,
Ye
S
.
Metformin inhibits extracellular matrix accumulation, inflammation and proliferation of mesangial cells in diabetic nephropathy by regulating H19/miR-143-3p/TGF-beta1 axis
.
J Pharm Pharmacol
.
2020 Aug
;
72
(
8
):
1101
9
.
2.
Cai
S
,
Chen
J
,
Li
Y
.
Dioscin protects against diabetic nephropathy by inhibiting renal inflammation through TLR4/NF-κB pathway in mice
.
Immunobiology
.
2020 Apr 19
;
225
:
151941
. .
3.
Toriu
N
,
Sawa
N
,
Imafuku
A
,
Hasegawa
E
,
Sekine
A
,
Mizuno
H
,
Rapidly progressive glomerulonephritis caused by tegafur/gimeracil/oteracil resulted in diabetes nephropathy, in a patient with minor risk of diabetes nephropathy: a case report
.
CEN Case Rep
.
2020 Nov
;
9
(
4
):
347
353
.
4.
Yu
S
,
Cheng
Y
,
Li
B
,
Xue
J
,
Yin
Y
,
Gao
J
,
M1 macrophages accelerate renal glomerular endothelial cell senescence through reactive oxygen species accumulation in streptozotocin-induced diabetic mice
.
Int Immunopharmacol
.
2020 Apr
;
81
:
106294
. .
5.
Chen
SJ
,
Lv
LL
,
Liu
BC
,
Tang
RN
.
Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease
.
Cell Prolif
.
2020 Mar
;
53
(
3
):
e12763
. .
6.
Potter
AS
,
Drake
K
,
Brunskill
EW
,
Potter
SS
.
A bigenic mouse model of FSGS reveals perturbed pathways in podocytes, mesangial cells and endothelial cells
.
PLoS One
.
2019
;
14
(
8
):
e0216261
. .
7.
Kamei
M
,
Matsuo
K
,
Imanishi
H
,
Hara
Y
,
Quen
YS
,
Kamiyama
F
,
Transcutaneous immunization with a highly active form of XCL1 as a vaccine adjuvant using a hydrophilic gel patch elicits long-term CD8(+) T cell responses
.
J Pharmacol Sci
.
2020 Jul
;
143
(
3
):
182
7
.
8.
Kim
J
,
Wang
S
,
Lee
C
,
Sung
S
,
Shin
Y
,
Song
KS
,
Blood-stage plasmodium berghei ANKA infection promotes hepatic fibrosis by enhancing hedgehog signaling in mice
.
Cell Physiol Biochem
.
2018
;
50
(
4
):
1414
28
. .
9.
Ewunkem
AJ
,
Deve
M
,
Harrison
SH
,
Muganda
PM
.
Diepoxybutane induces the expression of a novel p53-target gene XCL1 that mediates apoptosis in exposed human lymphoblasts
.
J Biochem Mol Toxicol
.
2020 Mar
;
34
(
3
):
e22446
. .
10.
Kwon
S
,
Ki
SM
,
Park
SE
,
Kim
MJ
,
Hyung
B
,
Lee
NK
,
Anti-apoptotic effects of human Wharton’s jelly-derived mesenchymal stem cells on skeletal muscle cells mediated via secretion of XCL1
.
Mol Ther
.
2016 Sep
;
24
(
9
):
1550
60
. .
11.
Botelho
NK
,
Tschumi
BO
,
Hubbell
JA
,
Swartz
MA
,
Donda
A
,
Romero
P
.
Combination of synthetic long peptides and XCL1 fusion proteins results in superior tumor control
.
Front Immunol
.
2019
;
10
:
294
. .
12.
Chou
WC
,
Hsiung
CN
,
Chen
WT
,
Tseng
LM
,
Wang
HC
,
Chu
HW
,
A functional variant near XCL1 gene improves breast cancer survival via promoting cancer immunity
.
Int J Cancer
.
2020 Apr 15
;
146
(
8
):
2182
93
. .
13.
Qi
C
,
Mao
X
,
Zhang
Z
,
Wu
H
.
Classification and differential diagnosis of diabetic nephropathy
.
J Diabetes Res
.
2017
;
2017
:
8637138
. .
14.
Papadopoulou-Marketou
N
,
Chrousos
GP
,
Kanaka-Gantenbein
C
.
Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis
.
Diabetes Metab Res Rev
.
2017 Feb
;
33
(
2
). .
15.
Lei
Y
,
Takahama
Y
.
XCL1 and XCR1 in the immune system
.
Microbes Infect
.
2012 Mar
;
14
(
3
):
262
7
. .
16.
Wang
Y
,
He
Z
,
Yang
Q
,
Zhou
G
.
XBP1 inhibits mesangial cell apoptosis in response to oxidative stress via the PTEN/AKT pathway in diabetic nephropathy
.
FEBS Open Bio
.
2019 Jul
;
9
(
7
):
1249
58
. .
17.
Bălăşescu
E
,
Ion
DA
,
Cioplea
M
,
Zurac
S
.
Caspases, cell death and diabetic nephropathy
.
Rom J Intern Med
.
2015 Oct–Dec
;
53
(
4
):
296
303
. .
18.
Wang
ZB
,
Zhang
S
,
Li
Y
,
Wang
RM
,
Tong
LC
,
Wang
Y
,
LY333531, a PKCβ inhibitor, attenuates glomerular endothelial cell apoptosis in the early stage of mouse diabetic nephropathy via down-regulating swiprosin-1
.
Acta Pharmacol Sin
.
2017 Jul
;
38
(
7
):
1009
23
. .
19.
Xu
L
,
Ren
Y
.
[Sitagliptin inhibits cell apoptosis and inflammation of renal tissues in diabetic nephropathy model rats]
.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
.
2019 Mar
;
35
(
3
):
217
22
.
20.
Kim
JS
,
Cho
IA
,
Kang
KR
,
Lim
H
,
Kim
TH
,
Yu
SK
,
Reversine induces caspase-dependent apoptosis of human osteosarcoma cells through extrinsic and intrinsic apoptotic signaling pathways
.
Genes Genomics
.
2019 Jun
;
41
(
6
):
657
65
. .
21.
Zhang
Y
,
Yang
X
,
Ge
X
,
Zhang
F
.
Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice
.
Biomed Pharmacother
.
2019 Jan
;
109
:
726
33
. .
22.
Ma
F
,
Wu
J
,
Jiang
Z
,
Huang
W
,
Jia
Y
,
Sun
W
,
P53/NRF2 mediates SIRT1’s protective effect on diabetic nephropathy
.
Biochim Biophys Acta Mol Cell Res
.
2019 Aug
;
1866
(
8
):
1272
81
. .
23.
Zhu
L
,
Han
J
,
Yuan
R
,
Xue
L
,
Pang
W
.
Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway
.
Biol Res
.
2018 Mar 31
;
51
(
1
):
9
. .
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