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Antioxidants
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Antioxidants and Their Role in Kidney Machine Perfusion and Kidney...
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Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 14024

Special Issue Editor

Dr. Christian Bleilevens

E-Mail Website
Guest Editor
Co-Founder and Chief Scientific Officer at Vivalyx GmbH, Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
Interests: in vitro perfusion systems; ischemia/reperfusion injury in vivo/in vitro; ECMO
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Localized and systemic ischemia reperfusion injury (IRI) remain clinically relevant issues. Following the heart and the brain, the kidney is the most vulnerable organ to IRI due to the high oxygen consumption of tubular transport processes. The regeneration mechanisms initiated by the onset of tubular damage caused by IRI often lead to irreversible interstitial fibrosis and, potentially, to the development of chronic kidney disease. Kidney transplantation procedures represent the ultimate scenario of ischemia and reperfusion, consisting of many steps that all contribute to organ damage through IRI: organ retrieval with a varying ischemia time, especially in donation after cardiac death; cold storage or varying perfusion (hypo-, subnormo-, normothermic);  persufflation strategies for organ transport; and finally, reperfusion during implantation. The formation of reactive oxygen species (ROS) is one of the major causes of organ damage during this process. Applying antioxidants is a promising strategy to prevent or limit ROS formation. Some of the recent topics in this field are the supplementation of organ perfusates with antioxidative vitamins or enzymes to catalyze processes with antioxidative potential, as well as the direct targeting of mitochondrial-triggered ROS formation. This Special Issue aims to collect papers that focus on the improvement of whole-kidney machine perfusion and kidney injury by applying antioxidant-based strategies

Dr. Christian Bleilevens
Guest Editor

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Keywords

  • kidney graft preservation
  • ex vivo kidney perfusion
  • in vitro kidney perfusion
  • antioxidants
  • kidney transplantation
  • kidney injury

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Published Papers (6 papers)

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Research

14 pages, 2236 KiB  
Article
Thiobarbiturate-Derived Compound MHY1025 Alleviates Renal Fibrosis by Modulating Oxidative Stress, Epithelial Inflammation, and Fibroblast Activation
by Jeongwon Kim, Jieun Lee, Dahye Yoon, Minjung Son, Mi-Jeong Kim, Sugyeong Ha, Doyeon Kim, Ji-an Yoo, Donghwan Kim, Hae Young Chung, Hyung Ryong Moon and Ki Wung Chung
Antioxidants 2023, 12(11), 1947; https://doi.org/10.3390/antiox12111947 - 31 Oct 2023
Viewed by 1080
Abstract
Chronic kidney disease (CKD) is a kidney structure and function abnormality. CKD development and progression are strongly influenced by oxidative stress and inflammatory responses, which can lead to tubulointerstitial fibrosis. Unfortunately, there are no effective or specific treatments for CKD. We investigated the [...] Read more.
Chronic kidney disease (CKD) is a kidney structure and function abnormality. CKD development and progression are strongly influenced by oxidative stress and inflammatory responses, which can lead to tubulointerstitial fibrosis. Unfortunately, there are no effective or specific treatments for CKD. We investigated the potential of the thiobarbiturate-derived compound MHY1025 to alleviate CKD by reducing oxidative stress and inflammatory responses. In vitro experiments using NRK52E renal tubular epithelial cells revealed that MHY1025 significantly reduced LPS-induced oxidative stress and inhibited the activation of the NF-κB pathway, which is involved in inflammatory responses. Furthermore, treatment with MHY1025 significantly suppressed the expression of fibrosis-related genes and proteins induced by TGFβ in NRK49F fibroblasts. Furthermore, we analyzed the MHY1025 effects in vivo. To induce kidney fibrosis, mice were administered 250 mg/kg folic acid (FA) and orally treated with MHY1025 (0.5 mg/kg/day) for one week. MHY1025 effectively decreased the FA-induced inflammatory response in the kidneys. The group treated with MHY1025 exhibited a significant reduction in cytokine and chemokine expression and decreased immune cell marker expression. Decreased inflammatory response was associated with decreased tubulointerstitial fibrosis. Overall, MHY1025 alleviated renal fibrosis by directly modulating renal epithelial inflammation and fibroblast activation, suggesting that MHY1025 has the potential to be a therapeutic agent for CKD. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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18 pages, 3471 KiB  
Article
Taurine as Antioxidant in a Novel Cell- and Oxygen Carrier-Free Perfusate for Normothermic Machine Perfusion of Porcine Kidneys
by Laura Zarnitz, Benedict M. Doorschodt, Lisa Ernst, Aisa Hosseinnejad, Eileen Edgworth, Tamara Fechter, Alexander Theißen, Sonja Djudjaj, Peter Boor, Rolf Rossaint, René H. Tolba and Christian Bleilevens
Antioxidants 2023, 12(3), 768; https://doi.org/10.3390/antiox12030768 - 21 Mar 2023
Cited by 1 | Viewed by 2199
Abstract
Donor organ-shortage has resulted in the increased use of marginal grafts; however, normothermic machine perfusion (NMP) holds the potential for organ viability assessment and restoration of marginal grafts prior to transplantation. Additionally, cell-, oxygen carrier-free and antioxidants-supplemented solutions could potentially prevent adverse effects [...] Read more.
Donor organ-shortage has resulted in the increased use of marginal grafts; however, normothermic machine perfusion (NMP) holds the potential for organ viability assessment and restoration of marginal grafts prior to transplantation. Additionally, cell-, oxygen carrier-free and antioxidants-supplemented solutions could potentially prevent adverse effects (transfusion reactions, inflammation, hemolysis), associated with the use of autologous packed red blood cell (pRBC)-based perfusates. This study compared 6 h NMP of porcine kidneys, using an established pRBC-based perfusate (pRBC, n = 7), with the novel cell- and oxygen carrier-free organ preservation solution Ecosol, containing taurine (Ecosol, n = 7). Despite the enhanced tissue edema and tubular injury in the Ecosol group, related to a suboptimal molecular mass of polyethylene glycol as colloid present in the solution, functional parameters (renal blood flow, intrarenal resistance, urinary flow, pH) and oxygenation (arterial pO2, absence of hypoxia-inducible factor 1-alpha) were similar to the pRBC group. Furthermore, taurine significantly improved the antioxidant capacity in the Ecosol group, reflected in decreased lactate dehydrogenase, urine protein and tubular vacuolization compared to pRBC. This study demonstrates the feasibility of 6 h NMP using a taurine containing, cell- and oxygen carrier-free perfusate, achieving a comparable organ quality to pRBC perfused porcine kidneys. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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15 pages, 2231 KiB  
Article
H2S-Enriched Flush out Does Not Increase Donor Organ Quality in a Porcine Kidney Perfusion Model
by Hanno Maassen, Leonie H. Venema, Marc G. Weiss, Tobias M. Huijink, H. Sijbrand Hofker, Anna K. Keller, Tom E. Mollnes, Marco Eijken, Søren E. Pischke, Bente Jespersen, Harry van Goor and Henri G. D. Leuvenink
Antioxidants 2023, 12(3), 749; https://doi.org/10.3390/antiox12030749 - 19 Mar 2023
Viewed by 1684
Abstract
Kidney extraction time has a detrimental effect on post-transplantation outcome. This study aims to improve the flush-out and potentially decrease ischemic injury by the addition of hydrogen sulphide (H2S) to the flush medium. Porcine kidneys (n = 22) were extracted [...] Read more.
Kidney extraction time has a detrimental effect on post-transplantation outcome. This study aims to improve the flush-out and potentially decrease ischemic injury by the addition of hydrogen sulphide (H2S) to the flush medium. Porcine kidneys (n = 22) were extracted during organ recovery surgery. Pigs underwent brain death induction or a Sham operation, resulting in four groups: donation after brain death (DBD) control, DBD H2S, non-DBD control, and non-DBD H2S. Directly after the abdominal flush, kidneys were extracted and flushed with or without H2S and stored for 13 h via static cold storage (SCS) +/− H2S before reperfusion on normothermic machine perfusion. Pro-inflammatory cytokines IL-1b and IL-8 were significantly lower in H2S treated DBD kidneys during NMP (p = 0.03). The non-DBD kidneys show superiority in renal function (creatinine clearance and FENa) compared to the DBD control group (p = 0.03 and p = 0.004). No differences were seen in perfusion parameters, injury markers and histological appearance. We found an overall trend of better renal function in the non-DBD kidneys compared to the DBD kidneys. The addition of H2S during the flush out and SCS resulted in a reduction in pro-inflammatory cytokines without affecting renal function or injury markers. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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19 pages, 5360 KiB  
Article
Oxidized-LDL Deteriorated the Renal Residual Function and Parenchyma in CKD Rat through Upregulating Epithelial Mesenchymal Transition and Extracellular Matrix-Mediated Tubulointerstitial Fibrosis—Pharmacomodulation of Rosuvastatin
by Pei-Hsun Sung, Ben-Chung Cheng, Tsuen-Wei Hsu, John Y Chiang, Hsin-Ju Chiang, Yi-Ling Chen, Chih-Chao Yang and Hon-Kan Yip
Antioxidants 2022, 11(12), 2465; https://doi.org/10.3390/antiox11122465 - 15 Dec 2022
Cited by 2 | Viewed by 1944
Abstract
This study tested the hypothesis that intrarenal arterial transfusion of oxidized low-density lipoprotein (ox-LDL) jeopardized the residual renal function and kidney architecture in rat chronic kidney disease ((CKD), i.e., induced by 5/6 nephrectomy) that was reversed by rosuvastatin. Cell culture was categorized into [...] Read more.
This study tested the hypothesis that intrarenal arterial transfusion of oxidized low-density lipoprotein (ox-LDL) jeopardized the residual renal function and kidney architecture in rat chronic kidney disease ((CKD), i.e., induced by 5/6 nephrectomy) that was reversed by rosuvastatin. Cell culture was categorized into A1 (NRK-52E cells), A2 (NRK-52E + TGF-β), A3 (NRK-52E + TGF-β + ox-LDL) and A4 (NRK-52E + TGF-β + ox-LD). The result of in vitro study showed that cell viability (at 24, 48 and 72 h), NRK-52E ox-LDL-uptake, protein expressions of epithelial–mesenchymal–transition (EMT) markers (i.e., p-Smad2/snail/α-SMA/FSP1) and cell migratory and wound healing capacities were significantly progressively increased from A1 to A4 (all p < 0.001). SD rats were categorized into group 1 (sham-operated control), group 2 (CKD), group 3 (CKD + ox-LDL/0.2 mg/rat at day 14 after CKD induction) and group 4 (CKD + ox-LDL-treated as group 3+ rosuvastatin/10 mg/kg/day by days 20 to 42 after CKD induction) and kidneys were harvested at day 42. The circulatory levels of BUN and creatinine, ratio of urine-protein to urine-creatinine and the protein expressions of the above-mentioned EMT, apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax) and oxidative-stress (NOX-1/NOX-2/oxidized-protein) markers were lowest in group 1, highest in group 3 and significantly higher in group 4 than in group 2 (all p < 0.0001). Histopathological findings demonstrated that the kidney injury score, fibrotic area and kidney injury molecule-1 (KIM-1) displayed an identical pattern, whereas the cellular expression of podocyte components (ZO-1/synaptopodin) exhibited an opposite pattern of EMT markers (all p < 0.0001). In conclusion, ox-LDL damaged the residual renal function and kidney ultrastructure in CKD mainly through augmenting oxidative stress, EMT and fibrosis that was remarkably reversed by rosuvastatin. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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28 pages, 5892 KiB  
Article
Tenovin-1 Ameliorates Renal Fibrosis in High-Fat-Diet-Induced Diabetic Nephropathy via Antioxidant and Anti-Inflammatory Pathways
by Amit Kundu, Sreevarsha Gali, Swati Sharma, Jae Hyeon Park, So Young Kyung, Sam Kacew, In Su Kim, Kwang Youl Lee and Hyung Sik Kim
Antioxidants 2022, 11(9), 1812; https://doi.org/10.3390/antiox11091812 - 14 Sep 2022
Cited by 9 | Viewed by 3082
Abstract
High-fat diet (HFD)-induced obesity has been involved in the development of diabetic nephropathy (DN). Tenovin-1, a potent selective SIRT1/2 inhibitor, regulates various target proteins. The present study evaluated the protective effect of Tenovin-1 against renal fibrosis in HFD-induced Zucker diabetic fatty (ZDF) rats. [...] Read more.
High-fat diet (HFD)-induced obesity has been involved in the development of diabetic nephropathy (DN). Tenovin-1, a potent selective SIRT1/2 inhibitor, regulates various target proteins. The present study evaluated the protective effect of Tenovin-1 against renal fibrosis in HFD-induced Zucker diabetic fatty (ZDF) rats. Rats were fed a normal chow diet or HFD. Tenovin-1 (45 mg/kg) administered to HFD-fed rats decreased inflammatory cytokine expression in the serum of the rats. The antioxidant status and oxidative damage to lipids or DNA were significantly restored by Tenovin-1. Additionally, Tenovin-1 reduced the levels of blood urea nitrogen (BUN), serum creatinine (sCr), microalbumin, and urinary protein-based biomarkers in the urine of HFD-fed rats. The abnormal architecture of the kidney and pancreas was restored by Tenovin-1 administration. Tenovin-1 also reduced apoptosis in the kidneys of the HFD-fed rats and HG-treated NRK-52E cells. It significantly lowered the levels of ECM proteins in the kidneys of HFD-fed rats and HG-treated NRK-52E cells. Additionally, Tenovin-1 markedly reduced claudin-1, SIRT1, and SIRT2, but increased SIRT3 and SIRT4 in HFD-fed rats and NRK-52E cells treated with HG. Furthermore, Tenovin-1 altered epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-β (PDGFR-β), and signal transducer and activator of transcription 3 (STAT3) levels in the kidneys of HFD-fed rats. Conclusively, this study shows that Tenovin-1 can be a potential candidate drug for the treatment of HFD-induced renal fibrosis, in vivo and in vitro models. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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Graphical abstract

16 pages, 4756 KiB  
Article
2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-β1 and p-ERK1/2 Axis
by Mohammed W. Al-Rabia, Mohamed A. Alfaleh, Hani Z. Asfour, Waleed S. Alharbi, Mohamed A. El-Moselhy, Nabil A. Alhakamy, Usama A. Fahmy, Osama A. A. Ahmed, Omar Fahmy, Omar M. Rashad, Abdulmohsin J. Alamoudi and Ashraf B. Abdel-Naim
Antioxidants 2022, 11(8), 1499; https://doi.org/10.3390/antiox11081499 - 30 Jul 2022
Cited by 3 | Viewed by 2196
Abstract
The immunosuppressant cyclosporine A (CSA) has been linked to serious renal toxic effects. Although 2-methoxyestradiol (2ME) possesses a wide range of pharmacological abilities, it suffers poor bioavailability after oral administration. The purpose of this study was to evaluate the potential of 2ME loaded [...] Read more.
The immunosuppressant cyclosporine A (CSA) has been linked to serious renal toxic effects. Although 2-methoxyestradiol (2ME) possesses a wide range of pharmacological abilities, it suffers poor bioavailability after oral administration. The purpose of this study was to evaluate the potential of 2ME loaded D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles to prevent CSA-induced nephrotoxicity in rats. A 2ME-TPGS was prepared and showed particle size of 44.3 ± 3.5 nm with good entrapment efficiency and spherical structures. Male Wistar rats were divided into 5 groups, namely: Control, Vehicle, CSA, CSA + 2ME-Raw, and CSA + 2ME-Nano. CSA was injected daily at a SC dose of 20 mg/kg. Both 2ME-Raw and 2ME-Nano were given daily at oral doses of 5 mg/kg. Treatments continued for three successive weeks. 2ME-TPGS exerted significant protective effects against CSA nephrotoxicity. This was evidenced in ameliorating deterioration of renal functions, attenuation of pathological changes in kidney tissues, exerting significant anti-fibrotic, antioxidant, and anti-inflammatory effects together with significant anti-apoptotic effects. Western blot analyses showed both 2ME-Raw and 2ME-Nano significantly inhibited protein expression of TGF-β1 and phospho-ERK (p-ERK). It was observed that 2ME-TPGS, in almost all experiments, exerted superior protective effects as compared with 2ME-Raw. In conclusion, 2ME loaded in a TPGS nanocarrier possesses significant protective activities against CSA-induced kidney injury in rats. This is attributable to 2ME anti-fibrotic, antioxidant, anti-inflammatory, and anti-apoptotic activities which are mediated at least partly by inhibition of TGF-β1/p-ERK axis. Full article
(This article belongs to the Special Issue Antioxidants and Their Role in Kidney Machine Perfusion and Kidney Injury)
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