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

Research output: Contribution to journalJournal Article peer-review

11 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 languageEnglish
Pages (from-to)100002-100020
Number of pages19
JournalOncotarget
Volume8
Issue number59
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Chen et al.

Keywords

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

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