Combined melatonin and exendin-4 therapy preserves renal ultrastructural integrity after ischemia-reperfusion injury in the male rat

• Published in: Journal of pineal research Vol. 59; no. 4; pp. 434 - 447
• Main Authors: Yip, Hon-Kan, Yang, Chih-Chao, Chen, Kuan-Hung, Huang, Tien-Hung, Chen, Yi-Ling, Zhen, Yen-Yi, Sung, Pei-Hsun, Chiang, Hsin-Ju, Sheu, Jiunn-Jye, Chang, Chia-Lo, Chen, Chih-Hung, Chang, Hsueh-Wen, Chen, Yen-Ta
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2015
• Subjects: Animals; Cadherins - metabolism; Calcium-Binding Proteins - metabolism; Cell Adhesion Molecules - metabolism; exendin-4; ischemia-reperfusion; Kidney - drug effects; Kidney - metabolism; kidney ultrastructure; Male; Matrix Metalloproteinase 9 - metabolism; melatonin; Melatonin - therapeutic use; NF-kappa B - metabolism; Oxidative Stress - drug effects; Peptides - therapeutic use; podocyte; Podocytes - drug effects; Podocytes - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Tumor Necrosis Factor-alpha - metabolism; Venoms - therapeutic use; WT1 Proteins - metabolism; ischemia-reperfusion; melatonin; exendin-4; kidney ultrastructure; podocyte
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/jpi.12273

We tested whether combined melatonin (Mel) and exendin‐4 (Ex4) treatment can better preserve glomerular structural integrity after ischemia–reperfusion (IR) injury compared with either alone. Adult male Sprague Dawley rats (n = 50) were equally divided into sham control (SC), IR, IR‐Ex4 (10 μg/kg subcutaneously 30 min after reperfusion and daily for 5 days), IR‐Mel (20 mg/kg intraperitoneally at 30 min postreperfusion and 50 mg/kg at 6 and 18 hr), and IR‐Ex4‐Mel were euthanized at day 14. Serum creatinine level and urine protein‐to‐creatinine ratio at days 3 and 14 were highest in IR group and lowest in SC, significantly higher in IR‐Ex4 and IR‐Mel groups than in IR‐Ex4‐Mel group (all P < 0.001) without significant difference between IR‐Ex4 and IR‐Mel groups. Changes in podocyte injury score (PIS) and kidney injury score were highest in IR group and lowest in SC, significantly higher in IR‐Ex4 and IR‐Mel groups than in IR‐Ex4‐Mel, and significantly higher in IR‐Mel group than in IR‐Ex4 group (all P < 0.001). Immunohistochemical microscopic findings of the expressions of FSP‐1 and WT‐1 (two glomerular damage indicators) and KIM‐1 and snail (two renal tubular‐damaged indicators) showed an identical pattern, whereas the expressions of ZO‐1, p‐cadherin, podocin, dystroglycan, fibronectin, and synaptopodin (six indices of glomerular integrity) demonstrated an opposite pattern compared to that of PIS among five groups (all P < 0.001). Protein expressions of inflammatory (TNF‐α/NF‐κB/MMP‐9) and oxidative stress (NOX‐1, NOX‐2, oxidized protein) biomarkers exhibited an identical pattern to that of PIS among five groups (all P < 0.001). Combined melatonin–exednin‐4 therapy further protected glomerulus from IR injury.