Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury.
This study tested whether combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSCs) offered additional benefit in ameliorating sepsis-induced acute kidney injury. Adult male Sprague-Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating TNF-α level at post-CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper-, cytoxic-, and regulatory-T cells at post-CLP 72 hr exhibited the same pattern as that of circulating TNF-α among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, and higher in CLP-A-ADMSC than in CLP-melatonin-A-ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF-1α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers, reactive-oxygen-species (NOX-1, NOX-2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO-1, NQO-1+) were lowest in SC group and highest in CLP-melatonin-A-ADMSC group, lower in CLP than in CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin- than in CLP-A-ADMSC-tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A-ADMSC was superior to A-ADMSC alone in protecting the kidneys from sepsis-induced injury.
Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Hong-Hwa
HH
Chen
Kun-Chen
KC
Lin
Christopher G
CG
Wallace
Yen-Ta
YT
Chen
Chih-Chao
CC
Yang
Steve
S
Leu
Yi-Ching
YC
Chen
Cheuk-Kwan
CK
Sun
Tzu-Hsien
TH
Tsai
Yung-Lung
YL
Chen
Sheng-Ying
SY
Chung
Chia-Lo
CL
Chang
Hon-Kan
HK
Yip
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D015153:Blotting, Western; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D018384:Oxidative Stress; D051381:Rats; D018805:Sepsis / Q000150:complications* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha
D014409:Tumor Necrosis Factor-alpha
acute kidney injury; adipose-derived mesenchymal stem cells; inflammation; melatonin; oxidative stress; sepsis syndrome