Enhanced protection against renal ischemia–reperfusion injury with combined melatonin and exendin-4 in a rodent model

Abstract

We tested the hypothesis that combined treatment with melatonin, an anti-oxidant, and exendin-4, an anti-inflammatory agent, was superior to either alone for protecting the kidney from ischemia-reperfusion (IR) injury. Male adult Sprague-Dawley rats (n¼40) were equally divided into group 1 (sham-operated control), group 2 (IR only, IR¼1h/72h), group 3 (IR-exendin-4, 10 mg/kg at 30 min, 24 h, 48 h after IR procedure), group 4 (IR-melatonin, i.p. 50 mg at 30 min, then 20 mg at 6 and 18 h after IR procedure), and group 5 (combined IR-exendin-4-melatonin). All animals were sacrificed by 72 h after IR/sham procedure. The results showed that the kidney injury score, plasma creatinine, and blood urea nitrogen (BUN) levels were highest in group 2 and lowest in group 1, significantly higher in groups 3 and 4 than those in group 5 and significantly higher in group 3 than those in group 4 (all p < 0.001). The protein expressions of inflammatory (toll-like receptor 4, inducible nitric oxide synthase, interleukin1b), apoptotic (mitochondrial Bax, cleaved caspase-3 and poly(ADP-ribose) polymerase, p53), podocyte integrity (E-cadherin, P-cadherin), and cell survival (phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin) biomarkers, as well the podocyte dysfunction biomarkers (Wnt1/Wnt4/b-catenin) displayed a pattern identical to that of creatinine level among the five groups (all p < 0.001). Microscopic findings demonstrated that podocyte dysfunction (Wnt1/Wnt4/b-catenin expression) and inflammatory (CD14 and F4/80-positively stained cells) biomarkers exhibited an identical pattern, whereas that of antioxidant (HO-1 þ , NQO-1 þ cells) biomarkers showed an opposite pattern compared to that of creatinine level among the five groups (all p < 0.001). Combined melatonin-exendin-4 therapy offered an additional benefit in protecting the kidney from acute IR injury.

Melatonin enhances survival and preserves functional integrity of stem cells: A review

“…Moreover, immunofluorescent microscopic findings of CD90+/53BP1+ and CD90+/XRCC1+ cells, two indicators of deoxyribonucleic acid (DNA) damage markers, were consistent with the pattern of apoptosis (Figure I‐N). Our findings from these studies help to explain the previous results from our experimental studies . Clearly, the molecular cellular protection by melatonin treatment played a crucial role in reducing the organ damage and facilitated the recovery of the organ function from both ischemia–reperfusion and sepsis syndrome situations.…”

“…Our previous experimental studies have shown that melatonin treatment significantly protects kidney, small bowel, lung, and liver, as well as urinary bladder against ischemia–reperfusion or sepsis syndrome‐induced injury or cyclophosphamide‐induced acute interstitial cystitis (Figure ). Additionally, combined melatonin–ADMSC therapy was superior to ADMSC alone for ameliorating damage of these organs …”

Melatonin prevents sepsis-induced renal injury via the PINK1/Parkin1 signaling pathway

“…MT has been demonstrated to exert anti-inflammatory effects in the skin, intestine, and the lungs; it can also assist in relieving chronic pelvic pain in women with endometriosis (32-34). It has been shown that, acting as an anti-apoptotic and anti-oxidization agent, MT can decrease the kidney damage induced by I-R, UUO, and severe burns (35-37). It has been shown that, by suppressing nucleocytoplasmic translocation, pretreatment with MT can enhance renal regeneration in folic acid-induced AKI, thus providing further insight on the treatment of AKI (38).…”

Bioactive Compounds for the Treatment of Renal Disease

“… 90 It has been reported that intraperitoneal injection of melatonin can reduce kidney damage induced by AKI and unilateral ureteral obstruction mainly through the antioxidant and anti-apoptotic effects. 91 92…”