Zinc preconditioning protects against renal ischaemia reperfusion injury in a preclinical sheep large animal model

Abstract

Ischaemia-reperfusion injury (IRI) during various surgical procedures, including partial nephrectomy for kidney cancer or renal transplantation, is a major cause of acute kidney injury and chronic kidney disease. Currently there are no drugs or methods for protecting human organs, including the kidneys, against the peril of IRI. The aim of this study was therefore to investigate the reno-protective effect of Zn preconditioning in a clinically relevant large animal sheep model of IRI. Further the reno-protective effectiveness of Zn preconditioning was tested on normal human kidney cell lines HK-2 and HEK293. Anaesthetised sheep were subjected to uninephrectomy and 60 min of renal ischaemia followed by reperfusion. Sheep were preconditioned with intravenous injection of zinc chloride prior to occlusion. Serum creatinine and urea were measured before ischaemia and for 7 days after reperfusion. HK-2 and HEK293 cells were subjected to in vitro IRI using the oxygen- and glucose-deprivation model. Zn preconditioning reduced ischaemic burden determined by creatinine and urea rise over time by ~ 70% in sheep. Zn preconditioning also increased the survival of normal human kidney cells subjected to cellular stress such as hypoxia, hydrogen peroxide injury, and serum starvation. Overall, our protocol incorporating specific Zn dosage, number of dosages (two), time of injection (24 and 4 h prior), mode of Zn delivery (IV) and testing of efficacy in a rat model, a large preclinical sheep model of IRI and cells of human origin has laid the foundation for assessment of the benefit of Zn preconditioning for human applications.

A pilot double‐blind safety and feasibility randomized controlled trial of high‐dose intravenous zinc in hospitalized COVID‐19 patients

“…Zinc and Zn‐salts inhibit viral infections in clinical and experimental settings, 1–10 including replication of SARS‐coronavirus (SARS‐CoV) 8 . Thus, zinc supplementation might be beneficial in patients with COVID‐19 11–17 . Clinical trials have been registered to test the efficacy of zinc against COVID, mostly with oral zinc supplementation 18 .…”

“…8 Thus, zinc supplementation might be beneficial in patients with COVID-19. [11][12][13][14][15][16][17] Clinical trials have been registered to test the efficacy of zinc against COVID, mostly with oral zinc supplementation. 18 However, the bioavailability of enterally administered zinc is low.…”

Biochemical Studies in Perfundates and Homogenates of Isolated Porcine Kidneys after Flushing with Zinc or Zinc–Prolactin Modified Preservation Solution Using a Static Cold Storage Technique

“…An improvement in serum blood urea nitrogen and creatinine concentrations was found [ 22 ]. O’Kane et al [ 23 ] investigated the renoprotective effect of Zn 2+ (doses of 0.1, 0.5, 1.0, 2.5, 10.0 mg/kg) preconditioning in a clinically relevant sheep model of IRI. Zinc upregulates hypoxia-inducible factor proteins.…”

Zinc supplementation as an adjunct therapy for COVID‐19: Challenges and opportunities

“…Based on zinc's ability to inhibit viral replication, mitigate the impact of dysregulation of the immune system, protect hypoxia-induced oxidative stress, and its anti-inflammatory properties, it is hypothesised that zinc supplementation would be beneficial in patients with COVID-19 infection. [16][17][18][19][20][21][22]…”

“…15 In the later stages of infection, zinc could be beneficial by mitigating the impact of dysregulation of the immune system, inflammation and hypoxia-induced oxidative stress. [16][17][18][19][20][21][22] Numerous studies have demonstrated that zinc modulates immune response, is anti-inflammatory, improves recovery of patients with severe pneumonia and is protective against hypoxia-induced ischaemia reperfusion injury. Therefore, this possibility that zinc can target multiple pathways driving the complex pathogenesis of COVID-19 infection has led to the hypothesis that zinc supplementation would be beneficial in COVID-19 patients.…”