Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats

Chih Hung Chen; Ben Chung Cheng; Kuan Hung Chen; Pei Lin Shao; Pei Hsun Sung; Hsin Ju Chiang; Chih Chao Yang; Kun Chen Lin; Cheuk Kwan Sun; Jiunn Jye Sheu; Hsueh Wen Chang; Mel S. Lee; Hon Kan Yip

doi:10.18632/oncotarget.21727

Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats

Chih Hung Chen
, Ben Chung Cheng
, Kuan Hung Chen
, Pei Lin Shao
, Pei Hsun Sung
, Hsin Ju Chiang
, Chih Chao Yang
, Kun Chen Lin
, Cheuk Kwan Sun
, Jiunn Jye Sheu
, Hsueh Wen Chang
, Mel S. Lee
, Hon Kan Yip^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

13 Scopus citations

Abstract

Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 10⁴) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC). At day 42 after CKD induction SS was induced. Thirty-minutes after SS induction, ADMSCs (2.0 ×10⁶ cells) were intravenously administered to groups 5 and 6. Ex4 (10 μg/ kg) was intraperitoneally administered groups 4 and 6 at 30 min and days 1 to 5 after SS induction. Animals were euthanized at day 47 after CKD induction. Kidneyinjury score, collagen-deposition area, and creatinine/BUN levels were lowest in group 1, highest in group 3 and significantly higher in group 2 than in groups 4 to 6 in a progressively increasing manner (all P < 0.0001). Protein expressions of inflammatory (MMP-9/TNF-α/NF-κB/IL-1β/ICAM-1), oxidative-stress (NOX-1/NOX- 2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP) and fibrotic/DNA-damaged (Smad3/TGF-β/γ-H2AX) biomarkers showed an identical pattern, whereas anti-fibrotic (BMP-2/Smad1/5), anti-apoptotic/endothelial-integrity (Bcl-2/eNOS) and podocyte-integrity (ZO-1/p-cadherin) biomarkers exhibited an opposite pattern of kidney-injury score among the six groups (all P > 0.0001). Cellular expressions of inflammatory (CD14/CD68) and glomerulus/tubular-injury (WT-1/ KIM-1) biomarkers displayed an identical pattern, whereas glomerulus/podocytecomponent (dystroglycan/nephrin/ZO-1/fibronectin/p-cadherin) biomarkers showed an opposite kidney-injury score among the six groups (all P < 0.0001). In conclusion, Ex4-ADMSC therapy effectively preserved renal function in the CKD-SS setting.

Original language	English
Pages (from-to)	100002-100020
Number of pages	19
Journal	Oncotarget
Volume	8
Issue number	59
DOIs	https://doi.org/10.18632/oncotarget.21727
State	Published - 2017

Bibliographical note

Publisher Copyright:
© Chen et al.

Keywords

Adipose-derived mesenchymal stem cell
Chronic kidney disease
Exendin-4
Inflammation
Sepsis syndrome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.21727

Cite this

Chen, C. H., Cheng, B. C., Chen, K. H., Shao, P. L., Sung, P. H., Chiang, H. J., Yang, C. C., Lin, K. C., Sun, C. K., Sheu, J. J., Chang, H. W., Lee, M. S., & Yip, H. K. (2017). Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats. Oncotarget, 8(59), 100002-100020. https://doi.org/10.18632/oncotarget.21727

@article{197aadd592cf42efbd012184e6c96528,

title = "Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats",

abstract = "Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC). At day 42 after CKD induction SS was induced. Thirty-minutes after SS induction, ADMSCs (2.0 ×106 cells) were intravenously administered to groups 5 and 6. Ex4 (10 μg/ kg) was intraperitoneally administered groups 4 and 6 at 30 min and days 1 to 5 after SS induction. Animals were euthanized at day 47 after CKD induction. Kidneyinjury score, collagen-deposition area, and creatinine/BUN levels were lowest in group 1, highest in group 3 and significantly higher in group 2 than in groups 4 to 6 in a progressively increasing manner (all P < 0.0001). Protein expressions of inflammatory (MMP-9/TNF-α/NF-κB/IL-1β/ICAM-1), oxidative-stress (NOX-1/NOX- 2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP) and fibrotic/DNA-damaged (Smad3/TGF-β/γ-H2AX) biomarkers showed an identical pattern, whereas anti-fibrotic (BMP-2/Smad1/5), anti-apoptotic/endothelial-integrity (Bcl-2/eNOS) and podocyte-integrity (ZO-1/p-cadherin) biomarkers exhibited an opposite pattern of kidney-injury score among the six groups (all P > 0.0001). Cellular expressions of inflammatory (CD14/CD68) and glomerulus/tubular-injury (WT-1/ KIM-1) biomarkers displayed an identical pattern, whereas glomerulus/podocytecomponent (dystroglycan/nephrin/ZO-1/fibronectin/p-cadherin) biomarkers showed an opposite kidney-injury score among the six groups (all P < 0.0001). In conclusion, Ex4-ADMSC therapy effectively preserved renal function in the CKD-SS setting.",

keywords = "Adipose-derived mesenchymal stem cell, Chronic kidney disease, Exendin-4, Inflammation, Sepsis syndrome",

author = "Chen, \{Chih Hung\} and Cheng, \{Ben Chung\} and Chen, \{Kuan Hung\} and Shao, \{Pei Lin\} and Sung, \{Pei Hsun\} and Chiang, \{Hsin Ju\} and Yang, \{Chih Chao\} and Lin, \{Kun Chen\} and Sun, \{Cheuk Kwan\} and Sheu, \{Jiunn Jye\} and Chang, \{Hsueh Wen\} and Lee, \{Mel S.\} and Yip, \{Hon Kan\}",

note = "Publisher Copyright: {\textcopyright} Chen et al.",

year = "2017",

doi = "10.18632/oncotarget.21727",

language = "英语",

volume = "8",

pages = "100002--100020",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

number = "59",

}

Chen, CH, Cheng, BC, Chen, KH, Shao, PL, Sung, PH, Chiang, HJ, Yang, CC, Lin, KC, Sun, CK, Sheu, JJ, Chang, HW, Lee, MS & Yip, HK 2017, 'Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats', Oncotarget, vol. 8, no. 59, pp. 100002-100020. https://doi.org/10.18632/oncotarget.21727

TY - JOUR

T1 - Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats

AU - Chen, Chih Hung

AU - Cheng, Ben Chung

AU - Chen, Kuan Hung

AU - Shao, Pei Lin

AU - Sung, Pei Hsun

AU - Chiang, Hsin Ju

AU - Yang, Chih Chao

AU - Lin, Kun Chen

AU - Sun, Cheuk Kwan

AU - Sheu, Jiunn Jye

AU - Chang, Hsueh Wen

AU - Lee, Mel S.

AU - Yip, Hon Kan

PY - 2017

Y1 - 2017

N2 - Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC). At day 42 after CKD induction SS was induced. Thirty-minutes after SS induction, ADMSCs (2.0 ×106 cells) were intravenously administered to groups 5 and 6. Ex4 (10 μg/ kg) was intraperitoneally administered groups 4 and 6 at 30 min and days 1 to 5 after SS induction. Animals were euthanized at day 47 after CKD induction. Kidneyinjury score, collagen-deposition area, and creatinine/BUN levels were lowest in group 1, highest in group 3 and significantly higher in group 2 than in groups 4 to 6 in a progressively increasing manner (all P < 0.0001). Protein expressions of inflammatory (MMP-9/TNF-α/NF-κB/IL-1β/ICAM-1), oxidative-stress (NOX-1/NOX- 2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP) and fibrotic/DNA-damaged (Smad3/TGF-β/γ-H2AX) biomarkers showed an identical pattern, whereas anti-fibrotic (BMP-2/Smad1/5), anti-apoptotic/endothelial-integrity (Bcl-2/eNOS) and podocyte-integrity (ZO-1/p-cadherin) biomarkers exhibited an opposite pattern of kidney-injury score among the six groups (all P > 0.0001). Cellular expressions of inflammatory (CD14/CD68) and glomerulus/tubular-injury (WT-1/ KIM-1) biomarkers displayed an identical pattern, whereas glomerulus/podocytecomponent (dystroglycan/nephrin/ZO-1/fibronectin/p-cadherin) biomarkers showed an opposite kidney-injury score among the six groups (all P < 0.0001). In conclusion, Ex4-ADMSC therapy effectively preserved renal function in the CKD-SS setting.

AB - Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC). At day 42 after CKD induction SS was induced. Thirty-minutes after SS induction, ADMSCs (2.0 ×106 cells) were intravenously administered to groups 5 and 6. Ex4 (10 μg/ kg) was intraperitoneally administered groups 4 and 6 at 30 min and days 1 to 5 after SS induction. Animals were euthanized at day 47 after CKD induction. Kidneyinjury score, collagen-deposition area, and creatinine/BUN levels were lowest in group 1, highest in group 3 and significantly higher in group 2 than in groups 4 to 6 in a progressively increasing manner (all P < 0.0001). Protein expressions of inflammatory (MMP-9/TNF-α/NF-κB/IL-1β/ICAM-1), oxidative-stress (NOX-1/NOX- 2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP) and fibrotic/DNA-damaged (Smad3/TGF-β/γ-H2AX) biomarkers showed an identical pattern, whereas anti-fibrotic (BMP-2/Smad1/5), anti-apoptotic/endothelial-integrity (Bcl-2/eNOS) and podocyte-integrity (ZO-1/p-cadherin) biomarkers exhibited an opposite pattern of kidney-injury score among the six groups (all P > 0.0001). Cellular expressions of inflammatory (CD14/CD68) and glomerulus/tubular-injury (WT-1/ KIM-1) biomarkers displayed an identical pattern, whereas glomerulus/podocytecomponent (dystroglycan/nephrin/ZO-1/fibronectin/p-cadherin) biomarkers showed an opposite kidney-injury score among the six groups (all P < 0.0001). In conclusion, Ex4-ADMSC therapy effectively preserved renal function in the CKD-SS setting.

KW - Adipose-derived mesenchymal stem cell

KW - Chronic kidney disease

KW - Exendin-4

KW - Inflammation

KW - Sepsis syndrome

UR - https://www.scopus.com/pages/publications/85034639833

U2 - 10.18632/oncotarget.21727

DO - 10.18632/oncotarget.21727

M3 - 文章

C2 - 29245956

AN - SCOPUS:85034639833

SN - 1949-2553

VL - 8

SP - 100002

EP - 100020

JO - Oncotarget

JF - Oncotarget

IS - 59

ER -

Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats

Abstract

Bibliographical note

Keywords

UN SDGs

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