Abstract
Abstract Renal ischemia/reperfusion (I/R) injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anticoagulants active site inhibited factor VIIa (ASIS) and activated protein C (APC) are besides their anticoagulant function also known for their cytoprotective properties. In this study the effect of ASIS and APC was assessed on renal I/R injury and this in relation to inflammation and apoptosis. Our results showed no effect of ASIS or APC on renal injury as determined by histopathological scoring as well as by blood urea nitrogen (BUN) and creatinine levels. Furthermore, no effect on fibrin staining was detected but ASIS did reduce tissue factor activity levels after a 2-hr reperfusion period. Neither ASIS nor APC administration influenced overall inflammation markers, although some inflammatory effects of ASIS on interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detectable after 2 hr of reperfusion. Finally, neither APC nor ASIS had an influence on cell signaling pathways or on the number of apoptotic cells within the kidneys. From this study we can conclude that the anticoagulants ASIS and APC do not have protective effects in renal I/R injury in the experimental setup as used in this study which is in contrast to the protective effects of these anticoagulants in other models of I/R.
Highlights
Renal ischemia/reperfusion (I/R) injury contributes in a large extent to kidney failure after organ transplantation [1]
Our results showed no effect of ASIS or activated protein C (APC) on renal injury as determined by histopathological scoring as well as by blood urea nitrogen (BUN) and creatinine levels
Renal function neither improved upon APC nor upon ASIS administration, as both BUN (Figure 1A) and creatinine (Figure 1B) plasma levels remained equal after APC (50.4 ± 1.6 mmol/l and 186.4 ± 4.1 mmol/l, respectively) or ASIS administration 2 min before induction of reperfusion and 15 min after induction of reperfusion (53.1 ± 1.5 mmol/l and 193.5 ± 4.6 mmol/l) compared to placebo administration (54.0 ± 1.3 mmol/l and 194.6 ± 3.5 mmol/l, respectively)
Summary
Renal ischemia/reperfusion (I/R) injury contributes in a large extent to kidney failure after organ transplantation [1]. Whether the process of inflammation is involved in the development of cell death or the other way around still remains a SOR-MED S.T.B.G. Loubele et al.: ASIS nor APC protects against renal I/R injury matter of debate [4,5,6]. We hypothesized that administration of APC or ASIS would protect against renal I/R injury via apoptosis and inflammation-regulated mechanisms. In contrast to previous studies [14, 17,18,19], in our experimental model only one kidney was clamped instead of two, while reperfusion of the clamped kidney was allowed after removal of the contra lateral kidney This approach is considered to be a good model for the clinical situation of ischemia reperfusion injury in a single transplanted kidney, which is one of the critical conditions related to renal I/R damage [4]. We investigated the effects of mouse APC and ASIS on early renal I/R injury, related to anticoagulant, antiinflammatory and anti-apoptotic mechanisms
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