Introduction: The exosomes from adipose-derived mesenchymal stem cells (AMSCs) had therapeutic effects. However, whether the exosomes derived from hypoxia-treated AMSCs could improve renal functions in unilateral ureteral obstruction (UUO) mice remains unclear. Methods: The exosomes were characterized using a transmission electron microscope and Western blot. Its size distribution was determined using the Zetasizer Nano ZS analysis system. The differentiation ability was assessed by alkaline phosphatase and oil red staining. Consequently, the function of exosomes in inhibiting inflammatory factors was evaluated using an enzyme-linked immunosorbent assay, and apoptosis inhibition was evaluated by Western blot. Finally, the function of exosomes to ameliorate kidney fibrosis was evaluated using quantitative reverse transcription polymerase chain reaction, Western blot, hematoxylin-eosin staining, and Masson staining. Results: The cultured AMSCs could differentiate into osteoblast and adipocyte. Meanwhile, the cultured AMSCs could effectively secrete the exosomes, which were characterized by around 110 nm diameter and surface marker expression. Exosomes derived from hypoxia-treated AMSCs improved renal functions in UUO mice. The mechanism exploration revealed that exosomes could decrease the TNF-α and IL-6 and inhibit cell apoptosis. Finally, the fibrosis-associated protein was reversed, and the renal dysfunctions were ameliorated in UUO mice. Conclusion: The exosomes derived from the hypoxia-treated AMSCs have a better effect than those from normal AMSCs in ameliorating renal dysfunctions in UUO mice.

1.
Romagnani
P
,
Remuzzi
G
,
Glassock
R
,
Levin
A
,
Jager
KJ
,
Tonelli
M
, et al
.
Chronic kidney disease
.
Nat Rev Dis Primers
.
2017
;
3
:
17088
.
2.
Panizo
S
,
Martinez-Arias
L
,
Alonso-Montes
C
,
Cannata
P
,
Martin-Carro
B
,
Fernandez-Martin
JL
, et al
.
Fibrosis in chronic kidney disease: pathogenesis and consequences
.
Int J Mol Sci
.
2021
;
22
(
1
):
408
.
3.
Zeisberg
M
,
Strutz
F
,
Muller
GA
.
Renal fibrosis: an update
.
Curr Opin Nephrol Hypertens
.
2001
;
10
(
3
):
315
20
.
4.
Wang
Z
,
Sun
D
.
Adipose-derived mesenchymal stem cells: a new tool for the treatment of renal fibrosis
.
Stem Cell Dev
.
2018
;
27
(
20
):
1406
11
.
5.
Hoseinynejad
K
,
Radan
M
,
Dianat
M
,
Nejaddehbashi
F
.
Adipose-derived mesenchymal stem cells protects renal function in a rat model of emphysema
.
Tissue Cell
.
2021
;
73
:
101613
.
6.
Eirin
A
,
Zhu
XY
,
Puranik
AS
,
Tang
H
,
McGurren
KA
,
van Wijnen
AJ
, et al
.
Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation
.
Kidney Int
.
2017
;
92
(
1
):
114
24
.
7.
Toyserkani
NM
,
Christensen
ML
,
Sheikh
SP
,
Sorensen
JA
.
Adipose-derived stem cells: new treatment for wound healing
.
Ann Plast Surg
.
2015
;
75
(
1
):
117
23
.
8.
Bratek-Gerej
E
,
Ziembowicz
A
,
Salinska
E
.
Group II metabotropic glutamate receptors reduce apoptosis and regulate BDNF and GDNF levels in hypoxic-ischemic injury in neonatal rats
.
Int J Mol Sci
.
2022
;
23
(
13
):
7000
.
9.
Chen
L
,
Wang
Y
,
Li
S
,
Zuo
B
,
Zhang
X
,
Wang
F
, et al
.
Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway
.
Theranostics
.
2020
;
10
(
20
):
9425
42
.
10.
Wang
Z
,
Li
S
,
Wang
Y
,
Zhang
X
,
Chen
L
,
Sun
D
.
GDNF enhances the anti-inflammatory effect of human adipose-derived mesenchymal stem cell-based therapy in renal interstitial fibrosis
.
Stem Cell Res
.
2019
;
41
:
101605
.
11.
Grosset
AA
,
Loayza-Vega
K
,
Adam-Granger
E
,
Birlea
M
,
Gilks
B
,
Nguyen
B
, et al
.
Hematoxylin and eosin counterstaining protocol for immunohistochemistry interpretation and diagnosis
.
Appl Immunohistochem Mol Morphol
.
2019
;
27
(
7
):
558
63
.
12.
Nazari Soltan Ahmad
S
,
Kalantary-Charvadeh
A
,
Hamzavi
M
,
Ezzatifar
F
,
Aboutalebi Vand Beilankouhi
E
,
Toofani-Milani
A
, et al
.
TGF-β1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways
.
J Mol Histol
.
2022
;
53
(
4
):
691
8
.
13.
Zhang
X
,
Zhang
Y
,
Yang
L
,
Wu
Y
,
Ma
X
,
Tong
G
, et al
.
IRF4 suppresses osteogenic differentiation of BM-MSCs by transcriptionally activating miR-636/DOCK9 axis
.
Clinics
.
2022
;
77
:
100019
.
14.
Bazargani
B
,
Moghtaderi
M
.
New biomarkers in early diagnosis of acute kidney injury in children
.
Avicenna J Med Biotechnol
.
2022
;
14
(
4
):
264
9
.
15.
Kalluri
R
,
Weinberg
RA
.
The basics of epithelial-mesenchymal transition
.
J Clin Invest
.
2009
;
119
(
6
):
1420
8
.
16.
Zeisberg
M
,
Neilson
EG
.
Mechanisms of tubulointerstitial fibrosis
.
J Am Soc Nephrol
.
2010
;
21
(
11
):
1819
34
.
17.
Webster
AC
,
Nagler
EV
,
Morton
RL
,
Masson
P
.
Chronic kidney disease
.
Lancet
.
2017
;
389
(
10075
):
1238
52
.
18.
Ruiz-Ortega
M
,
Rayego-Mateos
S
,
Lamas
S
,
Ortiz
A
,
Rodrigues-Diez
RR
.
Targeting the progression of chronic kidney disease
.
Nat Rev Nephrol
.
2020
;
16
(
5
):
269
88
.
19.
Lopez-Novoa
JM
,
Nieto
MA
.
Inflammation and EMT: an alliance towards organ fibrosis and cancer progression
.
EMBO Mol Med
.
2009
;
1
(
6–7
):
303
14
.
20.
Grande
MT
,
Lopez-Novoa
JM
.
Fibroblast activation and myofibroblast generation in obstructive nephropathy
.
Nat Rev Nephrol
.
2009
;
5
(
6
):
319
28
.
21.
Carney
EF
.
Chronic kidney disease: Key role of exosomes in albumin-induced inflammation
.
Nat Rev Nephrol
.
2018
;
14
(
3
):
142
.
22.
Gallo
S
,
Gili
M
,
Lombardo
G
,
Rossetti
A
,
Rosso
A
,
Dentelli
P
, et al
.
Stem cell-derived, microRNA-carrying extracellular vesicles: a novel approach to interfering with mesangial cell collagen production in a hyperglycaemic setting
.
PLoS One
.
2016
;
11
(
9
):
e0162417
.
23.
Wang
B
,
Yao
K
,
Huuskes
BM
,
Shen
HH
,
Zhuang
J
,
Godson
C
, et al
.
Mesenchymal stem cells deliver exogenous MicroRNA-let7c via exosomes to attenuate renal fibrosis
.
Mol Ther
.
2016
;
24
(
7
):
1290
301
.
24.
Teshima
T
,
Okamoto
K
,
Dairaku
K
,
Nagashima
T
,
Michishita
M
,
Suzuki
R
, et al
.
Generation of insulin-producing cells from canine adipose tissue-derived mesenchymal stem cells
.
Stem Cell Int
.
2020
;
2020
:
8841865
.
25.
Shi
Y
,
Wang
Y
,
Li
Q
,
Liu
K
,
Hou
J
,
Shao
C
, et al
.
Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases
.
Nat Rev Nephrol
.
2018
;
14
(
8
):
493
507
.
26.
Chen
L
,
Xiang
E
,
Li
C
,
Han
B
,
Zhang
Q
,
Rao
W
, et al
.
Umbilical cord-derived mesenchymal stem cells ameliorate nephrocyte injury and proteinuria in a diabetic nephropathy rat model
.
J Diabetes Res
.
2020
;
2020
:
8035853
.
27.
Maumus
M
,
Peyrafitte
JA
,
D'Angelo
R
,
Fournier-Wirth
C
,
Bouloumie
A
,
Casteilla
L
, et al
.
Native human adipose stromal cells: localization, morphology and phenotype
.
Int J Obes
.
2011
;
35
(
9
):
1141
53
.
28.
Zuk
PA
,
Zhu
M
,
Mizuno
H
,
Huang
J
,
Futrell
JW
,
Katz
AJ
, et al
.
Multilineage cells from human adipose tissue: implications for cell-based therapies
.
Tissue Eng
.
2001
;
7
(
2
):
211
28
.
29.
Horwitz
EM
,
Le Blanc
K
,
Dominici
M
,
Mueller
I
,
Slaper-Cortenbach
I
,
Marini
FC
, et al
.
Clarification of the nomenclature for MSC: the international society for cellular therapy position statement
.
Cytotherapy
.
2005
;
7
(
5
):
393
5
.
30.
Kern
S
,
Eichler
H
,
Stoeve
J
,
Kluter
H
,
Bieback
K
.
Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue
.
Stem Cell
.
2006
;
24
(
5
):
1294
301
.
31.
Mitchell
JB
,
McIntosh
K
,
Zvonic
S
,
Garrett
S
,
Floyd
ZE
,
Kloster
A
, et al
.
Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers
.
Stem Cell
.
2006
;
24
(
2
):
376
85
.
32.
Shen
Z
,
Huang
W
,
Liu
J
,
Tian
J
,
Wang
S
,
Rui
K
.
Effects of mesenchymal stem cell-derived exosomes on autoimmune diseases
.
Front Immunol
.
2021
;
12
:
749192
.
33.
He
J
,
Wang
Y
,
Lu
X
,
Zhu
B
,
Pei
X
,
Wu
J
, et al
.
Micro-vesicles derived from bone marrow stem cells protect the kidney both in vivo and in vitro by microRNA-dependent repairing
.
Nephrology
.
2015
;
20
(
9
):
591
600
.
34.
Gatti
S
,
Bruno
S
,
Deregibus
MC
,
Sordi
A
,
Cantaluppi
V
,
Tetta
C
, et al
.
Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury
.
Nephrol Dial Transplant
.
2011
;
26
(
5
):
1474
83
.
35.
Xiang
E
,
Han
B
,
Zhang
Q
,
Rao
W
,
Wang
Z
,
Chang
C
, et al
.
Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis
.
Stem Cell Res Ther
.
2020
;
11
(
1
):
336
.
36.
Ren
HW
,
Yu
W
,
Wang
YN
,
Zhang
XY
,
Song
SQ
,
Gong
SY
, et al
.
Effects of autophagy inhibitor 3-methyladenine on a diabetic mice model
.
Int J Ophthalmol
.
2023
;
16
(
9
):
1456
64
.
37.
Tkach
M
,
Thery
C
.
Communication by extracellular vesicles: where we are and where we need to go
.
Cell
.
2016
;
164
(
6
):
1226
32
.
38.
Syn
N
,
Wang
L
,
Sethi
G
,
Thiery
JP
,
Goh
BC
.
Exosome-Mediated metastasis: from epithelial-mesenchymal transition to escape from immunosurveillance
.
Trends Pharmacol Sci
.
2016
;
37
(
7
):
606
17
.
39.
van Niel
G
,
D’Angelo
G
,
Raposo
G
.
Shedding light on the cell biology of extracellular vesicles
.
Nat Rev Mol Cell Biol
.
2018
;
19
(
4
):
213
28
.
40.
Valadi
H
,
Ekstrom
K
,
Bossios
A
,
Sjostrand
M
,
Lee
JJ
,
Lotvall
JO
.
Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells
.
Nat Cell Biol
.
2007
;
9
(
6
):
654
9
.
41.
Milane
L
,
Singh
A
,
Mattheolabakis
G
,
Suresh
M
,
Amiji
MM
.
Exosome mediated communication within the tumor microenvironment
.
J Control Release
.
2015
;
219
:
278
94
.
42.
Atienzar-Aroca
S
,
Flores-Bellver
M
,
Serrano-Heras
G
,
Martinez-Gil
N
,
Barcia
JM
,
Aparicio
S
, et al
.
Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells
.
J Cell Mol Med
.
2016
;
20
(
8
):
1457
66
.
43.
King
HW
,
Michael
MZ
,
Gleadle
JM
.
Hypoxic enhancement of exosome release by breast cancer cells
.
BMC Cancer
.
2012
;
12
:
421
.
44.
Umezu
T
,
Tadokoro
H
,
Azuma
K
,
Yoshizawa
S
,
Ohyashiki
K
,
Ohyashiki
JH
.
Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1
.
Blood
.
2014
;
124
(
25
):
3748
57
.
45.
Park
H
,
Park
H
,
Mun
D
,
Kang
J
,
Kim
H
,
Kim
M
, et al
.
Extracellular vesicles derived from hypoxic human mesenchymal stem cells attenuate GSK3β expression via miRNA-26a in an ischemia-reperfusion injury model
.
Yonsei Med J
.
2018
;
59
(
6
):
736
45
.
46.
Yu
B
,
Kim
HW
,
Gong
M
,
Wang
J
,
Millard
RW
,
Wang
Y
, et al
.
Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection
.
Int J Cardiol
.
2015
;
182
:
349
60
.
47.
Zhang
Y
,
Qin
W
,
Zhang
L
,
Wu
X
,
Du
N
,
Hu
Y
, et al
.
MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis
.
Sci Rep
.
2015
;
5
:
9401
.
48.
Yu
W
,
Zeng
H
,
Chen
J
,
Fu
S
,
Huang
Q
,
Xu
Y
, et al
.
miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury
.
Clin Sci
.
2020
;
134
(
16
):
2223
34
.
49.
Olarewaju
O
,
Hu
Y
,
Tsay
HC
,
Yuan
Q
,
Eimterbaumer
S
,
Xie
Y
, et al
.
MicroRNA miR-20a-5p targets CYCS to inhibit apoptosis in hepatocellular carcinoma
.
Cell Death Dis
.
2024
;
15
(
6
):
456
.
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