BACKGROUND Acute kidney injury (AKI) secondary to renal ischemia and reperfusion (I/R) injury is widely prevalent. Ghrelin, a stomach-derived peptide, has been shown to be anti-inflammatory. The purpose of this study was to examine whether human ghrelin has any beneficial effects after renal I/R injury and if so, whether ghrelin’s action in renal I/R injury is mediated by the vagus nerve. METHODS Male adult rats were subjected to renal I/R by bilateral renal pedicle clamping for 60 min, treated intravenously with human ghrelin (4 nmol/rat) or normal saline (vehicle) immediately following reperfusion. After 24 h, the animals were euthanized, and samples were harvested. In eparate groups, subdiaphragmatic vagotomy prior to renal I/R was performed, treated with human ghrelin or vehicle, and at 24 h, blood and organs were harvested. RESULTS Renal I/R injury caused significant increases in the serum levels of tissue injury markers as compared to sham operation. Human ghrelin treatment significantly attenuated serum creatinine and BUN, by 55% and 53%, and liver enzymes (AST and ALT) by 20% and 24%, respectively as compared to vehicle-treated groups. Tissue water contents, plasma and kidney IL-6 and kidney MPO activity were reduced. Bcl-2/Bax ratio was increased, and histology of the kidneys was improved. More importantly, prior vagotomy abolished ghrelin’s protective effect in tissue injury markers and tissue water contents in renal I/R injured animals. CONCLUSION Human ghrelin treatment in renal I/R injured rats attenuated systemic and kidney specific inflammatory responses. The protection of human ghrelin in renal I/R injury was mediated by the vagus nerve. These data suggest ghrelin can be developed as a novel treatment for patients with AKI induced by renal I/R injury.
Background Acute renal failure secondary to ischemia and reperfusion (I/R) injury poses a significant burden on both surgeons and patients. It carries a high morbidity and mortality rate and no specific treatment currently exists. Major causes of renal I/R injury include trauma, sepsis, hypoperfusion, and various surgical procedures. We have demonstrated that adrenomedullin (AM), a novel vasoactive peptide, combined with AM binding protein-1 (AMBP-1), which augments the activity of AM, is beneficial in various disease conditions. However, it remains unknown whether human AM/AMBP-1 provides any beneficial effects in renal I/R injury. The objective of our study therefore was to determine whether administration of human AM/AMBP-1 can prevent and/or minimize damage in a rat model of renal I/R injury. Methods Male adult rats were subjected to renal I/R injury by bilateral renal pedicle clamping with microvascular clips for 60 min followed by reperfusion. Human AM (12 µg/kg BW) and human AMBP-1 (40 µg/kg BW) or vehicle (52 µg/kg BW human albumin) were given intravenously over 30 min immediately following the clip removal (i.e., reperfusion). Rats were allowed to recover for 24 h post treatment, and blood and renal tissue samples were collected. Plasma levels of AM were measured using a radioimmunoassay specific for rat AM. Plasma AMBP-1 was measured by Western analysis. Renal water content and serum levels of systemic markers of tissue injury were measured. Serum and renal TNF-α levels were also assessed. Results At 24 h after renal I/R injury, plasma levels of AM were significantly increased while plasma AMBP-1 was markedly decreased. Renal water content and systemic markers of tissue injury (e.g., creatinine, BUN, AST and ALT) were significantly increased following renal I/R injury. Serum and renal TNF-α levels were also increased post injury. Administration of human AM/AMBP-1 decreased renal water content, and plasma levels of creatinine, BUN, AST and ALT. Serum and renal TNF-α levels were also significantly decreased after AM/AMBP-1 treatment. Conclusion Treatment with human AM/AMBP-1 in renal I/R injury significantly attenuated organ injury and the inflammatory response. Thus, human AM combined with human AMBP-1 may be developed as a novel treatment for patients with acute renal I/R injury.
Background The liver is a major organ that is susceptible to injury following blunt and/or penetrating trauma to the abdomen. No specific non-operative treatment exists for traumatic hepatic injury (THI). Adrenomedullin (AM), a vasoactive peptide, combined with its binding protein (AMBP-1) is beneficial in various disease conditions. In this study, we propose to determine whether human AM combined with human AMBP-1 provides benefit in a model of THI in the rat. Methods Male adult rats were subjected to trauma-hemorrhage by resection of approximately 50% of total liver tissues and allowed bleeding for 15 min. Immediately thereafter, human AM (48 μg/kg BW) plus human AMBP-1 (160 μg/kg BW) was given intravenously over 30 min in 1 ml normal saline. After 4 h, the rats were euthanized, blood was collected, and tissue injury indicators were assessed. A 10-day survival study was also conducted. Results At 4 h after THI, plasma AMBP-1 levels were markedly decreased. Plasma levels of liver injury indicators (i.e., AST, ALT and LDH) were significantly increased after THI. Likewise, lactate, creatinine and TNF-α levels were significantly increased following THI. Administration of human AM/AMBP-1 after THI produced significant decreases of 64%, 23% and 19% of plasma AST, ALT and LDH levels, respectively. Similarly, plasma levels of lactate, creatinine and TNF-α were also decreased by 42%, 28% and 46% following human AM/AMBP-1 treatment, respectively. In a 10-day survival study, while vehicle treatment produced 41% survival, human AM/AMBP-1 treatment improved the survival rate to 81%. Conclusions Administration of human AM/AMBP-1 significantly attenuated tissue injury and inflammation, and improved survival following THI. Thus, human AM/AMBP-1 can be developed as a novel treatment for victims with uncontrolled traumatic hemorrhage.
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