Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model

Abstract

IntroductionIschemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up.MethodsUnilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI.ResultsUnilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function.ConclusionsAs expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I.

Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice

“…While the results of this study are promising and are consistent with other ischemia/reperfusion experiments in other organ systems [29,30,45,46], the detailed mechanism of action of danegaptide is not fully elucidated [46] and requires further study…”

“…Danegaptide is a small orally available therapeutic peptide that exhibits protective characteristics under ischemia/reperfusion injury, in different tissue types [30,45]. To investigate whether danegaptide could be protective in stroke, mice were therapeutically treated with the drug under an ischemia/reperfusion stroke model tMCAO.…”

The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43

“…Both rotigaptide and ZP1609 decrease myocardial infarct size in dog and pig hearts when administered before reperfusion (Hennan et al, ; Hennan et al, ; Skyschally et al, ; Pedersen et al, ). In a model of renal I/R injury, however, ZP1609 did not improve renal function (Amdisen et al, ).…”

Assessment of neutrophil gelatinase-associated lipocalin as an early biomarker for canine renal ischemia-reperfusion injury

“…Mechanical ventilation was maintained with 40% oxygen and a tidal volume of 10 mL/kg. Expiratory CO 2 was maintained at a level of 4.5-5.5 kPa (20).…”