Kidney Ischemia-reperfusion Research Articles

The Hepatoprotective Effect of Peroxiredoxin 6 in Ischemia–Reperfusion Kidney Injury

The Hepatoprotective Effect of Peroxiredoxin 6 in Ischemia–Reperfusion Kidney Injury

Long-Term Protection of CHBP Against Combinational Renal Injury Induced by Both Ischemia-Reperfusion and Cyclosporine A in Mice.

Renal ischemia–reperfusion (IR) injury and cyclosporine A (CsA) nephrotoxicity affect allograft function and survival. The prolonged effects and underlying mechanisms of erythropoietin derived cyclic helix B peptide (CHBP) and/or caspase-3 small interfering RNA (CASP-3siRNA) were investigated in mouse kidneys, as well as kidney epithelial cells (TCMK-1), subjected to transplant-related injuries. Bilateral renal pedicles were clamped for 30 min followed by reperfusion for 2 and 8 weeks, with/without 35 mg/kg CsA gavage daily and/or 24 nmol/kg CHBP intraperitoneal injection every 3 days. The ratio of urinary albumin to creatinine was raised by IR injury, further increased by CsA and lowered by CHBP at 2, 4, 6 and 8 weeks, whereas the level of SCr was not significantly affected. Similar change trends were revealed in tubulointerstitial damage and fibrosis, HMGB1 and active CASP-3 protein. Increased apoptotic cells in IR kidneys were decreased by CsA and CHBP at 2 and/or 8 weeks. p70 S6 kinase and mTOR were reduced by CsA with/without CHBP at 2 weeks, so were S6 ribosomal protein and GSK-3β at 8 weeks, with reduced CASP-3 at both time points. CASP-3 was further decreased by CHBP in IR or IR + CsA kidneys at 2 or 8 weeks. Furthermore, in TCMK-1 cells CsA induced apoptosis was decreased by CHBP and/or CASP-3siRNA treatment. Taken together, CHBP predominantly protects kidneys against IR injury at 2 weeks and/or CsA nephrotoxicity at 8 weeks, with different underlying mechanisms. Urinary albumin/creatinine is a good biomarker in monitoring the progression of transplant-related injuries. CsA divergently affects apoptosis in kidneys and cultured kidney epithelial cells, in which CHBP and/or CASP-3siRNA reduces inflammation and apoptosis.

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability.

Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia-inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.

Oxidative stress following acute kidney injury causes disruption of lung cell cilia and their release into the bronchoaveolar lavage fluid and lung injury, which are exacerbated by Idh2 deletion

Acute kidney injury (AKI) induces distant organ injury, which is a serious concern in patients with AKI. Recent studies have demonstrated that distant organ injury is associated with oxidative stress of organ and damage of cilium, an axoneme-based cellular organelle. However, the role of oxidative stress and cilia damage in AKI-induced lung injury remains to be defined. Here, we investigated whether AKI-induced lung injury is associated with mitochondrial oxidative stress and cilia disruption in lung cells. AKI was induced in isocitrate dehydrogenase 2 (Idh2, a mitochondrial antioxidant enzyme)-deleted (Idh2−/−) and wild-type (Idh2+/+) mice by kidney ischemia-reperfusion (IR). A group of mice were treated with Mito-TEMPO, a mitochondria-specific antioxidant. Kidney IR caused lung injuries, including alveolar septal thickening, alveolar damage, and neutrophil accumulation in the lung, and increased protein concentration and total cell number in bronchoalveolar lavage fluid (BALF). In addition, kidney IR caused fragmentation of lung epithelial cell cilia and the release of fragments into BALF. Kidney IR also increased the production of superoxide, lipid peroxidation, and mitochondrial and nuclei DNA oxidation in lungs and decreased IDH2 expression. Lung oxidative stress and injury relied on the degree of kidney injury. Idh2 deletion exacerbated kidney IR-induced lung injuries. Treatment with Mito-TEMPO attenuated kidney IR-induced lung injuries, with greater attenuation in Idh2−/− than Idh2+/+ mice. Our data demonstrate that AKI induces the disruption of cilia and damages cells via oxidative stress in lung epithelial cells, which leads to the release of disrupted ciliary fragments into BALF.

SIRT1 alleviates kidney ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-mediated autophagy

Objective(s): Renal ischemia-reperfusion (IR) injury is a therapeutic challenge for surgeons. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that plays a vital role in modulating cellular senescence and aging. In this study, we determined whether SIRT1 up-regulation could alleviate renal IR injury and the underlying mechanism. Materials and Methods: A renal IR model was induced in male C57BL/6 mice. Blood urea nitrogen and serum creatinine were evaluated as markers of kidney function, and renal injury was assessed by pathological examination. The inflammatory milieu was analyzed by real-time RT-PCR and myeloperoxidase immunofluorescence assays. Western blotting was used to quantify SIRT1 protein expression, endoplasmic reticulum stress, and autophagy. Results: SIRT1 was up-regulated in renal tissue after IR. Blood analysis and histopathological examination demonstrated that SIRT1 preserved renal function and reduced renal damage. Further evaluations illustrated that IR induced autophagy and endoplasmic reticulum stress, while SIRT1 up-regulation reduced endoplasmic reticulum stress-mediated autophagy levels. Conclusion: SIRT1 up-regulation protects the kidney against IR-induced injury by inhibiting endoplasmic reticulum stress-mediated autophagy.

Micro-RNA-486-5p protects against kidney ischemic injury and modifies the apoptotic transcriptome in proximal tubules

Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI.

Effect of NAD+ boosting on kidney ischemia-reperfusion injury.

Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD+) with progressing fibrosis resulting in CKD. NAD+ is a co-enzyme for several proteins, including the NAD+ dependent sirtuins. NAD+ augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD+, caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin (postn) and Inhibin subunit beta-A, (activin A / Inhba), both 24 hours and 14 days after surgery. NR restored tissue NAD+ to that of the sham group, increased autophagy (reduced p62) and sirtuin1 (Sirt1) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD+ depletion and impaired autophagy, while augmentation of NAD+ by NR restored tissue NAD+ and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis.

MO468NEW URINARY BIOMARKERS DETECT SUBCLINICAL RENAL DAMAGE AFTER SEVERAL ACUTE KIDNEY INJURY EPISODES

Abstract Background and Aims Acute kidney injury (AKI) represents a clinical problem due to its increasing prevalence and association with further morbidities. Observational studies have shown that AKI increases the risk of a new AKI episode, chronic kidney disease (CKD), CKD progression, end-stage renal disease (ESRD), and mortality. Serum creatinine (sCr) is the parameter most used by clinicians for determining AKI and the subsequent recovery, however its use presents several limitations. sCr lacks sensitivity for AKI and provides minimal insight into the renal structure. Indeed, increases in sCr are observed only when glomerular filtration rate decreases more than 50%. Therefore, new markers need to be identified to predict recovery after AKI and to detect residual structural alterations that can cause progression to CKD. We hypothesised that after AKI, there are renal structural abnormalities that cannot be detected by common clinical parameters but may be detected by urinary biomarkers. Method We used 4 weeks old male Wistar rats. Animals were divided into 5 experimental groups: Control group: SHAM operated rats, saline solution i.p.; “CDDP5-SHAM” group: 5 mg/kg cisplatin i.p.; “Ctrl-I/R60” group: 60-minute renal ischemia reperfusion in the left kidney; “CDDP5-I/R60” group: 5 mg/kg cisplatin i.p. and after renal function normalization, 60-minute ischemia-reperfusion (I/R60); “5/6 NEF” group: 5/6 nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and every week thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Urinary biomarkers were analyzed at day 20 (12 days after the second damage and 20 after the first one) by western blot and ELISA. Animals were sacrificed at the same time point in which urinary biomarkers were determined, and renal tissue samples were stained with Masson´s trichrome, Sirius Red and Periodic Acid-Schiff for histological analysis. Results Frequency of AKI episodes is related to the amount and degree of subclinical alterations detected in the kidneys, even though renal filtration is apparently normal. We characterized a novel panel of urinary biomarkers (bk1-bk4) several days after the last insult (day 20) when renal function appeared normal; these biomarkers were present in highest concentrations in the CDDP5-I/R60 experimental group. Conclusion These results demonstrate the importance of the clinical implementation of biomarkers as useful tools for medical support and underline the limitations of the clinical parameters (e.g. sCr, estimated GFR) currently used for renal function assessment. The frequency of AKI episodes is related to a poor prognosis, so a follow up is necessary after AKI episodes in order to prevent mortality and progression of the disease.

Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury

Ischemia-reperfusion injury is a major cause of acute kidney injury. Recent studies on the pathophysiology of ischemia-reperfusion-induced acute kidney injury showed that immunologic responses significantly affect kidney ischemia-reperfusion injury and repair. Nuclear factor (NF)-ĸB signaling, which controls cytokine production and cell survival, is significantly involved in ischemia-reperfusion-induced acute kidney injury, and its inhibition can ameliorate ischemic acute kidney injury. Using EXPLOR, a novel, optogenetically engineered exosome technology, we successfully delivered the exosomal super-repressor inhibitor of NF-ĸB (Exo-srIĸB) into B6 wild type mice before/after kidney ischemia-reperfusion surgery, and compared outcomes with those of a control exosome (Exo-Naïve)-injected group. Exo-srIĸB treatment resulted in lower levels of serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin in post-ischemic mice than in the Exo-Naïve treatment group. Systemic delivery of Exo-srIĸB decreased NF-ĸB activity in post-ischemic kidneys and reduced apoptosis. Post-ischemic kidneys showed decreased gene expression of pro-inflammatory cytokines and adhesion molecules with Exo-srIĸB treatment as compared with the control. Intravital imaging confirmed the uptake of exosomes in neutrophils and macrophages. Exo-srIĸB treatment also significantly affected post-ischemic kidney immune cell populations, lowering neutrophil, monocyte/macrophage, and T cell frequencies than those in the control. Thus, modulation of NF-ĸB signaling through exosomal delivery can be used as a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

Mechanistic Evaluation of Linalool Effect against Renal Ischemia- Reperfusion Injury in Rats.

Kidney ischemia reperfusion (IR) is an important cause of renal dysfunction. The hypoxic conditions in ischemic damage result in the formation of free radicals and apoptotic death of renal cells. We evaluated the renoprotective effects of linalool in IR- induced renal injury. Wistar rats were divided into three groups of six rats; namely, control group, IR group, and linalool + IR group. The animals were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. Linalool (40mg/kg) was administered before ischemia. After 24h reperfusion, the kidney tissues were obtained for detection of miR-21, HSP 70 and caspase-3 expression levels and histological studies. Also, the blood samples were collected for the measurement of biochemical parameters. IR significantly increased the expression of miR-21, HSP70 and capase-3 and the serum levels of BUN-Cr, ALT, AST and ALP enzymes. Furthermore, histological findings of the IR group confirmed that there were acute tubular necrosis and lymphocyte infiltration in the renal tissues. Treatment with linalool improved the renal function and morphological changes. It seems that linalool could exert a nephroprotective effect via a number of mechanisms in renal IR injury.

Mas Receptor Blockade Promotes Renal Vascular Response to Ang II after Partial Kidney Ischemia/Reperfusion in a Two-Kidney-One-Clip Hypertensive Rats Model.

Background Partial kidney ischemia-reperfusion (IR) injury is the principal cause of acute kidney injury. The renin-angiotensin system (RAS) and hypertension also may be influenced by renal IR injury. In two models of partial renal IR with and without ischemia preconditioning (IPC) and using Mas receptor (MasR) blockade, A779 or its vehicle, the renal vascular responses to angiotensin II (Ang II) administration in two-kidney-one-clip (2K1C) hypertensive rats were determined. Methods Thirty-seven 2K1C male Wistar rats with systolic blood pressure ≥150 mmHg were randomly divided into three groups; sham, IR, and IPC + IR. The animals in the sham group underwent surgical procedures except partial IR. The rats in the IR group underwent 45 min partial kidney ischemia, and the animals in the IPC + IR group underwent two 5 min cycles of partial kidney ischemia followed by 10 min reperfusion and partial kidney ischemia for 45 min. The renal vascular responses to graded Ang II (30, 100, 300, and 1000 ng kg−1.min−1) infusion using A779 or its vehicle were measured at constant renal perfusion pressure. Results Four weeks after 2K1C implementation, the intravenous infusion of graded Ang II resulted in dose-related increases in mean arterial pressure (MAP) (Pdose < 0.0001) that was not different significantly between the groups. No significant differences were detected between the groups in renal blood flow (RBF) or renal vascular resistance (RVR) responses to Ang II infusion when MasR was not blocked. However, by MasR blockade, these responses were increased in IR and IPC + IR groups that were significantly different from the sham group (P < 0.05). For example, infusion of Ang II at dose 1000 ng kg−1.min−1 resulted in decreased RBF percentage change (RBF%) from the baseline to 17.5 ± 1.9%, 39.7 ± 3.8%, and 31.0 ± 3.4% in sham, IR, and IPC + IR, respectively. Conclusion These data revealed the important role of MasR after partial kidney IR in the responses of RBF and RVR to Ang II administration in 2K1C hypertensive rats.

Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury

Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing ischemic acute kidney injury (AKI). Sex-related differences in mitochondrial function and homeostasis exist, likely contributing to sexual dimorphism in kidney injury, but the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, a major mitochondrial acetyltransferase) in the kidneys of male mice versus females. We tested the hypothesis that differential expression of kidney Sirt3 may mediate sexual dimorphism in AKI using a bilateral kidney ischemia-reperfusion injury (IRI) model and three transgenic mouse models: (1) mice with global transgenic overexpression of Sirt3; (2) mice with inducible, kidney tubule-specific Sirt3 knockdown (iKD); and (3) mice with global Sirt3 knockout. Low mitochondrial Sirt3 (mtSirt3) in males versus females is associated with development of kidney tubular epithelium vacuoles, increased mitochondrial ROS and susceptibility to IRI. Transgenic overexpression of Sirt3 in males protects against kidney IRI and development of tubular epithelium vacuoles. In both sexes, mice with partial kidney tubular epithelium-specific Sirt3 knockdown display intermediate - while global Sirt3 knockout mice display the highest susceptibility to IRI. Female Sirt3 iKD mice demonstrate decreased survival and kidney function after IRI indistinguishable from control males, abolishing the protective effects observed in females. Mechanistically, observed differences in kidney mtSirt3 are sex hormone-dependent; estradiol increases - while testosterone decreases mtSirt3 protein. Our results demonstrate that Sirt3 is an important contributor to the observed sex-related differences in IRI susceptibility, and a potential therapeutic target in the clinical management of AKI.

Mechanisms of Adiponectin in Regulation of Proinflammatory Cytokine Production and Migration in Macrophages.

IntroductionEvidence indicate that adiponectin may exert pro-inflammatory effects on inflammatory cells. We have found that adiponectin knockout decreased inflammatory reaction and tubular damage in the ischemia-reperfusion kidney in APN-knockout mice. Globular adiponectin and full-length adiponectin (g-APN and f-APN) were used in this study to investigate the effects of adiponectin on proinflammatory cytokines production and migration in Raw 264.7 cells.MethodsProinflammatory cytokines production was detected by real-time RT-PCR. NF-kappaB activation was interrupted through Ad-DN-IκBα or SN-50 to confirm how g-APN induces proinflammatory cytokines production. The siRNA against AdipoR1 and AdipoR2 was investigated to uncover the signaling pathway that may involve in NF-kappaB activation and migration in Raw 264.7 cells.Resultsg-APN, not f-APN, was found triggering the production of inflammatory cytokine MIP-2, IL-6, TNFα, and MCP-1 in Raw 264.7 cells. NF-kappaB Inhibition by Ad-DN-IκBα expression or cell-permeable NF-κB inhibitor SN-50 could decrease NF-kappaB nuclear translocation and subsequently decrease inflammatory cytokine expression triggered by globular ANP. However, AdipoR1 and AdipoR2 were not found involved in NF-kappaB activation in this study. Full-length APN, not g-APN, was involved in the promotion of macrophage migration. The migration induced by full-length APN could be inhibited by knockdown of AdipoR1 expression with siRNA. The migration effect could also be inhibited by PI3Kγ inhibitor, AS-605240.DiscussionThese results suggested that full-length adiponectin increases macrophage migration through Adiponectin-AdipoR1-PI3Kgamma signaling pathway. However, NF-κB activation induced by g-APN in this study was independent of AdipoR1 or AdipoR2. The exact signaling pathway of NF-κB activation by adiponectin should be further studied to find a new anti-inflammatory target.

Gut Microbiota-Immune System Interactions during Acute Kidney Injury.

Distant organ crosstalk during AKI, first studied mechanistically in the lung (1), is now known to play an important role in disease outcomes. The relationship between intestinal microbiota and AKI has also been explored, resulting in exciting findings that are promising for future human therapeutics. In search of ways to reduce kidney T cells by using “cleaner,” germfree (GF) mice, it was unexpectedly found that GF mice not only retained their kidney immune cells, but also had a higher number of natural killer T (NKT) cells and reduced IL-4 levels compared with normal wild-type (WT) mice. Moreover, GF mice subjected to kidney ischemia-reperfusion (IR) injury had increased CD8 T-cell trafficking and inflammatory cytokine mediators compared with normal WT mice (2). Induction of ischemic AKI in GF mice led to a worse course of AKI, in terms of both structure and function. Conventionalizing GF mice with normal mouse stool led to normalizing T-cell and NKT populations, and relative protection from AKI, compared with GF mice (2). It was subsequently observed that early exposure to gut microbiota during development was associated with long-term changes in NKT-cell function in nonrenal tissues, and NKT cells in GF mice had a less mature phenotype with diminished activation capacity upon antigen encounter (3,4). To elucidate whether the effects were bidirectional and AKI led to changes in the gut microbiome, gut microbiota was evaluated in C57BL/6 WT mice after ischemic or nephrotoxic (cisplatin; CP) injury. DNA was isolated from the fecal pellets ( n =4–5 per group) at baseline (D0) and at 3 days (D3) post-IR. The V3–V5 region of the 16S ribosomal RNA gene was amplified using the 357F/926R primer set and sequenced using the Roche/454 platform. IR and CP modified the relative abundance of specific bacterial species belonging to the phyla Actinobacteria, Bacteroidetes, Firmicutes, …

Restoration of afferent arteriolar autoregulatory behavior in ischemia-reperfusion injury in rat kidneys.

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.NEW & NOTEWORTHY Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury.

Comparison of the Preventive Effects of Carvedilol and Nebivolol on Kidney Ischemia Reperfusion Injury

Comparison of the Preventive Effects of Carvedilol and Nebivolol on Kidney Ischemia Reperfusion Injury

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

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.&#x0D; 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.&#x0D; 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.&#x0D; Conclusion: Pharmacological preconditioning with carbamylated darbepoetin and udenafil reduces the severity of acute kidney injury induced by ischemia-reperfusion.

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.

Синергизм карбамилированного дарбэпоэтина и Л-этоксидола в модели экспериментальной ишемии почки

AIM to determine the efficiency of different doses of erythropoietin and carbamylated darbepoetin, to prove experimentally the possibility of increasing the efficiency of carbamylated darbepoetin when using the levorotatory stereoisomer of ethoxidol. MATERIALS AND METHODS On the model of ischemia-reperfusion injury in male CD-1 mice that were undergone to contralateral nephrectomy, the nephroprotective effect of different doses of erythropoietin alfa, carbamylated darbepoetin, L-ethoxidol (the levorotatory enantiomer of ethylmethylhydroxypyridine malate), and the combined use of L-ethapylated carboxypyridine malate and L-etapoietin alfa was studied. The parameters of microcirculation and glomerular filtration rate were studied one day after 30-minute ischemia. RESULTS It has been established that the prophylactic use of erythropoietin alfa and carbamylated darbepoetin in the model of ischemia-reperfusion injury of a single kidney reduces the severity of microcirculatory impairment and ensures the preservation of the glomerular filtration rate in dose-dependent manner. The synergistic effect of L-ethoxidol and carbamylated darbepoetin was found when these substances were used together. CONCLUSION Prevention of ischemia-reperfusion kidney injury by analogs of human erythropoietin and their combination with ethylmethylhydroxypyridine derivatives is experimentally-proved.

Protective effects of Gamma Oryzanol on distant organs after kidney ischemia-reperfusion in rats: A focus on liver protection.

Acute kidney injury (AKI) is the main clinical concern resulted from ischemia-reperfusion injury (IRI). Ample clinical data indicates that AKI is associated with distant organ dysfunctions and poor patients' outcomes. Oxidative stress and inflammation have a critical role in the pathogenesis of organ injuries following IRI. The objectives of this study were to determine the impact of Gamma Oryzanol (GO), extracted from rice bran oil, on distant organs in rats after IRI. Twelve out of 24 Wistar rats were treated by one dosage of GO (100mg/kg) 1 h before I/R induction through both oral gavage and intraperitoneal injection. Then, the AKI model rats were induced by IRI. Oxidative stress and antioxidant protein levels were assessed in the brain, heart, and liver tissues in the experimental groups. Furthermore, the effects of GO on IRI-induced liver dysfunction, apoptosis, and inflammation were measured by Western blot. GO pretreatment could significantly restore the levels and activity of antioxidant proteins in the brain, heart, and liver tissues (P < 0.05). Moreover, GO pretreatment could decrease the inflammatory cytokine (IL-1, IL-6, and TNF-α) in the liver (P < 0.01). By reducing Bax/Bcl-2 ratio and down-regulating caspase-3, GO could significantly diminish apoptosis in the liver tissue after the kidney I/R (P < 0.01). Additionally, GO could significantly diminish the deterioration of liver function in the kidney I/R model. GO protects distant organs against renal IRI-induced oxidative stress. Furthermore, it ameliorates liver function and remarkably exerts anti-oxidative, anti-inflammatory, and anti-apoptotic roles in the liver as an important detoxifying organ.