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.