Combined therapy with melatonin and exendin-4 effectively attenuated the deterioration of renal function in rat cardiorenal syndrome.
This study tested the hypothesis that combined therapy with melatonin (Mel) and exendin-4 (Ex4) would be superior to either therapy alone for preventing the deterioration of renal function in cardiorenal syndrome (CRS). Male adult Sprague Dawley rats (n = 48) were randomly and equally divided into sham-control (SC), chronic kidney disease (CKD; induced by 5/6 nephrectomy), CRS (CKD + dilated cardiomyopathy, DCM; induced by doxorubicin 7 mg/kg i.p. every 5 days, 4 doses), CRS-Mel (20 mg/kg/day), CRS-Ex4 (10 µg/kg/day) and CRS-Mel-Ex4. They were euthanized by day 60 after CRS induction. By day 60, plasma creatinine level, urine protein/creatinine ratio and kidney injury histopathology score were highest in CRS, lowest in SC, and progressively decreased from CKD, CRS-Mel, CRS-Ex4 to CRS-Mel-Ex4 (all P<0.0001). The kidney protein expressions of inflammation (TNF-α/NF-κB/MMP-9/iNOS/RANTES), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), apoptosis (cleaved caspase-3/cleaved PARP/Bax), DNA-damaged marker (γ-H2AX) and fibrosis (p-mad3/TFG-β) showed identical patterns of creatinine level, whereas kidney protein expressions of GLP-1R showed a progressive increase from SC to CRS-Mel-Ex4 (all P<0.0001). Cellular expressions of inflammatory (CD14/CD68), DNA/kidney-damaged (γ-H2AX/KIM-1) and podocyte/renal tubule dysfunction signaling (β-catenin/Wnt1/Wnt4) biomarkers in kidney tissue exhibited an identical pattern of creatinine level (all P<0.0001). Podocyte components (podocin/dystroglycan/p-cadherin/synatopodin) were highest in SC, lowest in CRS, and significantly progressively increased from CKD to CRS-Mel-Ex4 (all P<0.0001). In conclusion, combined Mel-Ex4 therapy was superior to either one alone in preserving renal-function and kidney architectural integrity in the setting of CRS.
Department of Biological Sciences, National Sun Yat-sen UniversityKaohsiung 80424, Taiwan; Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung UniversityKaohsiung 83301, Taiwan.
Kuan-Hung
KH
Chen
Division of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Chih-Hung
CH
Chen
Department of Plastic Surgery, Royal Devon & Exeter Hospital Exeter, EX2 5DW, United Kingdom.
Christopher Glenn
CG
Wallace
Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Yen-Ta
YT
Chen
Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Chih-Chao
CC
Yang
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Pei-Hsun
PH
Sung
Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Hsin-Ju
HJ
Chiang
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Yi-Ling
YL
Chen
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University Kaohsiung 83301, Taiwan.
Sarah
S
Chua
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung UniversityKaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical UniversityTaichung 40402, Taiwan; Department of Nursing, Asia UniversityTaichung 41354, Taiwan.
Hon-Kan
HK
Yip
Department of Biological Sciences, National Sun Yat-sen University Kaohsiung 80424, Taiwan.
Jiin-Tsuey
JT
Cheng
Cardiorenal syndrome; exendin-4; melatonin; renal function impairment