Renoprotective effect of carbamylated darbepoetin and udenafil in ischemia-reperfusion of rat kidney due to the effect of preconditioning and inhibition of nuclear factor kappa B

Abstract

Introduction: Acute kidney injury is a widespread complication in hospitalized patients, with a high mortality rate and long-term complications affecting prognosis and quality of life and with high human and financial costs. In addition, to date, no clear algorithm for the prevention of this type of damage has been developed. Materials and methods: The research was carried out on male Wistar rats. A 40-minute renal ischemia-reperfusion model was used to model acute kidney injury. Further, the renoprotective properties of carbamylated darbepoetin, udenafil and their combination were assessed based on the analysis of the biochemical studies’ results, dynamics of the renal status and the renal microvasculature, and the pathomorphological picture. A series of experiments was also carried out to assess the contribution of adenosine triphosphate-dependent potassium channels and nuclear factor kappa B to the renoprotective properties of the said agents. Results and discussion: Prophylactic administration of carbamylated darbepoetin at a dose of 50 µg/kg and udenafil at a dose of 8.7 mg/kg led to a statistically significant decrease in creatinine and blood urea nitrogen, an increase in glomerular filtration rate with a simultaneous decrease in fractional excretion of sodium, as well as an increase in the level of microcirculation in the kidneys and a decrease in the severity of damage according to the data of a pathomorphological examination at all time points of the experiment. A higher efficiency of correcting ischemic and reperfusion renal injuries was observed when using a combination of the said pharmacological agents. A series of experiments with glibenclamide demonstrated that its preliminary administration levels the renoprotective properties of carbamylated darbepoetin and udenafil. The ability of the studied pharmacological agents to reduce lipopolysaccharide-induced expression of nuclear factor kappa B in mononuclear cells was also demonstrated. The results of the research suggest that the renoprotective effects of carbamylated darbepoetin, udenafil, and their combination are realized through ATP-dependent potassium channels and nuclear factor kappa B. Conclusion: Pharmacological preconditioning with carbamylated darbepoetin and udenafil reduces the severity of acute kidney injury induced by ischemia-reperfusion. Graphical abstract:

Potential of Sodium-Glucose Cotransporter Inhibitors as Agents for Prevention of Ischemic and Reperfusion Kidney Injury

“…One of the key mechanisms for the realization of their protective effects, researchers call the activation of the reverse tubuloglomerular connection, which leads to a decrease in hyperfiltration, one of the key pathogenetic links of kidney injury in diabetes mellitus, chronic kidney disease, and arterial hypertension 17, 28 . On the contrary, tubuloglomerular feedback is one of the components damaging kidney tissue in ischemic and reperfusion injuries, as it leads to glomerular vasospasm, which makes a significant contribution to the decrease in GFR in AKI 29 . In this regard, it was suggested that SGLT-2 inhibitors may increase the risk of developing AKI, which has been demonstrated in some studies 28 .…”

Коррекция Ишемических И Реперфузионных Повреждений Почек При Сочетанном Применении Инфликсимаба И Пептида, Имитирующего Α-Спираль B Эритропоэтина

“…1 group - The activity of the erythropoietin mimetic peptide (pHBSP) (provided by a pharmaceutical company PHARMAPARK LLC) was studied at the doses of 5 mcg/ kg and 25 mcg/kg; the activity of infliximab (Remicade, MSD) was studied at the doses of 2 mg/kg and 10 mg/kg; the activity of recombinant erythropoietin (Epocrine, Research Institute of Highly Pure Biopreparations, Russia) was studied at the dose of 50 IU/kg; the activity of glibenclamide (Maninil, Berlin-Chemie AG, Germany) was studied at the dose of 5 mg/kg. These doses were selected based on previously identified protective effects on ischemia/reperfusion models or were calculated taking into account the recommended human doses using conversion factors (Nagata et al 2016;Kostina et al 2021;Firsova et al 2022). The dose schedule is based on the pharmacokinetic profile of the drug.…”

NEPHROPROTECTIVE EFFECT OF A COMBINATION OF THE PEPTIDE MIMICKING THE a-SPATIAL STRUCTURE OF THE p ERYTHROPOIETIN CHAIN AND INFLIXIMAB IN RENAL ISCHEMIA-REPERFUSION INJURY

“…Одними из наиболее перспективных препаратов для коррекции ишемически-реперфузионной травмы почек являются эритропоэтин и его производные [1,2]. Активация гетеродимерного рецептора обуславливает развитие цитопротективных эффектов [3,4].…”