Exendin-4-assisted adipose derived mesenchymal stem cell therapy protects renal function against co-existing acute kidney ischemia-reperfusion injury and severe sepsis syndrome in rat

Pei Hsun Sung, Hsin Ju Chiang, Christopher Glenn Wallace, Chih Chao Yang, Yen Ta Chen, Kuan Hung Chen, Chih Hung Chen, Pei Lin Shao, Yung Lung Chen, Sarah Chua, Han Tan Chai, Yi Ling Chen, Tien Hung Huang, Hon Kan Yip, Mel S. Lee*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

25 Scopus citations

Abstract

This study tested the hypothesis that combined therapy with exendin-4 (Ex4) and autologous adipose-derived mesenchymal stem cells (ADMSCs) was superior to either alone for protecting renal function against acute kidney ischemia-reperfusion (IR; 40-min ischemia/27-h reperfusion) injury when complicated by sepsis syndrome (SS; by cecal-ligation-puncture). Adult-male Sprague-Dawley rats (n=40) were equally divided into group 1 (sham-control), group 2 (IR-SS), group 3 (IR-SS + Ex4, 10 μg/kg subcutaneously 30 min after reperfusion and daily for 3 days), group 4 [IR-SS + ADMSC (1.2 × 106)], and group 5 (IR-SS + Ex4 + ADMSC). The circulating levels of BUN and creatinine and the ratio of urine protein to creatinine were highest in group 2, lowest in group 1, significantly higher in groups 3 and 4 than group 5, and significantly higher in group 3 than in group 4 (all P<0.0001). Microscopic findings of kidney injury score, inflammatory cells (CD14+, F4/80+), and expressions of glomerular-damage indicators (FSP-1+/WT-1+) and renal tubular-damage indicators (KIM-1+/snail+) showed an identical pattern, whereas expressions of indices of glomerular-integrity (ZO-1+/p-cadherin+/podocin+/synaptopodin+) and angiogenesis (CD31+/vWF+/ number of small vessels) biomarkers demonstrated an opposite pattern, to that of creatinine level (all P<0.001). Protein expressions of inflammatory (MMP-9/IL-1ß/TNF-α/TLR-2/TLR-4), apoptotic (cleaved caspase-3/PARP/mi-tochondrial Bax), and oxidative-stress (NOX-1/NOX-2/oxidized protein) biomarkers exhibited an identical pattern, whereas anti-inflammatory (IL-10/IL-4) biomarkers displayed an opposite pattern, to that of creatinine level (all P<0.001). In conclusion, combined Ex4 and ADMSC therapy significantly protected kidney from acute IR-SS injury.

Original languageEnglish
Pages (from-to)3167-3183
Number of pages17
JournalAmerican Journal of Translational Research
Volume9
Issue number7
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017, E-Century Publishing Corporation. All rights reserved.

Keywords

  • Adipose derived mesenchymal stem cells
  • Exendin-4
  • Ischemia-reperfusion injury
  • Oxidative stress
  • Sepsis syndrome

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