Rat Model Of Renal Ischemia-reperfusion Injury Research Articles

Inhibition of both NOX and TNF-α exerts substantial renoprotective effects in renal ischemia reperfusion injury rat model

Background and aimsAcute kidney injury (AKI) due to renal ischemia-reperfusion injury (RIRI) is associated with high morbidity and mortality, with no renoprotective drug available. Previous research focused on single drug targets, yet this approach has not reached translational success. Given the complexity of this condition, we aimed to identify a disease module and apply a multitarget network pharmacology approach. MethodsIdentification of a disease module with potential drug targets was performed utilizing Disease Module Detection algorithm using NADPH oxidases (NOXs) as seeds. We then assessed the protective effect of a multitarget network pharmacology targeting the identified module in a rat model of RIRI. Rats were divided into five groups; sham, RIRI, and RIRI treated with setanaxib (NOX inhibitor, 10 mg/kg), etanercept (TNF-α inhibitor, 10 mg/kg), and setanaxib and etanercept (5 mg/kg each). Kidney functions, histopathological changes and oxidative stress markers (MDA and reduced GSH) were assessed. Immunohistochemistry of inflammatory (TNF-α, NF-κB) apoptotic (cCasp-3, Bax/Bcl 2), fibrotic (α-SMA) and proteolysis (MMP-9) markers was performed. ResultsOur in-silico analysis yielded a disease module with TNF receptor 1 (TNFR1A) as the closest target to both NOX1 and NOX2. Targeting this module by a low-dose combination of setanaxib, and etanercept, resulted in a synergistic effect and ameliorated ischemic AKI in rats. This was evidenced by improved kidney function and reduced expression of inflammatory, apoptotic, proteolytic and fibrotic markers. ConclusionsOur findings show that applying a multitarget network pharmacology approach allows synergistic renoprotective effect in ischemic AKI and might pave the way towards translational success.

Role of Iberin as an anti-apoptotic agent on renal ischemia-reperfusion injury in rats.

Ischemia-reperfusion injury (IRI) is a major contributor to acute and chronic kidney failure, heart failure, and ischemic stroke. This study aimed to investigate the therapeutic potential of Iberin, known for its anti-inflammatory, antioxidant, and antiapoptotic properties, in a rat model of renal IRI. Twenty-four adult male rats were randomly divided into four groups: Group I (Sham group) underwent laparotomy without IRI induction; Group II (Control group) underwent laparotomy followed by renal artery clamping for 30 minutes to induce ischemia, followed by 2 hours of reperfusion; Group III (Iberin treatment group) received a pre-injection of Iberin (15 mg/kg) and underwent 30 minutes of ischemia followed by 2 hours of reperfusion; and Group IV (Vehicle-treated group) received the vehicle (ethanol) 1 hour prior to ischemia and reperfusion induction. Iberin was diluted with ethanol. Biomarkers associated with inflammation, oxidative stress, and apoptosis were measured using enzyme-linked immunosorbent assay. Iberin treatment significantly reduced levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-6, Bcl-2-associated X protein (BAX), tumor necrosis factor α (TNF-α), nuclear factor kappa p56, high mobility group B1, and neutrophil gelatinase-associated lipocalin. Moreover, Iberin increased levels of heat shock protein and Bcl2 compared to the control and vehicle groups. Iberin treatment prolonged the ischemic tolerance of renal tissue, potentially preventing or delaying irreversible injuries. These findings highlight the potential of Iberin as a promising candidate for mitigating renal injury caused by ischemia-reperfusion, due to its ability to modulate inflammatory markers.

The Effect of Nerolidol Renal Dysfunction following Ischemia-Reperfusion Injury in the Rat.

Efforts to decrease the deleterious effects of renal ischemia-reperfusion injury (IRI) are ongoing. Recently, there has been increasing interest in using natural phytochemical compounds as alternative remedies in several diseases. Nerolidol is a natural product extracted from plants with floral odors and has been proven to be effective for the treatment of some conditions. We investigated the effect of nerolidol in a rat model of renal IRI. Nerolidol was dissolved in a vehicle and administered orally as single daily dose of 200 mg/kg for 5 days prior to IRI and continued for 3 days post IRI. G-Sham (n = 10) underwent sham surgery, whereas G-IRI (n = 10) and G-IRI/NR (n = 10) underwent bilateral warm renal ischemia for 30 min and received the vehicle/nerolidol, respectively. Renal functions and histological changes were assessed before starting the medication, just prior to IRI and 3 days after IRI. Nerolidol significantly attenuated the alterations in serum creatinine and urea, creatinine clearance, urinary albumin and the urinary albumin-creatinine ratio. Nerolidol also significantly attenuated the alterations in markers of kidney injury; proinflammatory, profibrotic and apoptotic cytokines; oxidative stress markers; and histological changes. We conclude that nerolidol has a renoprotective effect on IRI-induced renal dysfunction. These findings might have clinical implications.

Agathis robusta Bark Extract Protects from Renal Ischemia-Reperfusion Injury: Phytochemical, In Silico and In Vivo Studies.

Background: Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (RIRI) is associated with a high incidence of mortality. Existing therapies are mainly supportive, with no available nephroprotective agent. The purpose of this study is to examine the potential protective effect of Agathis robusta Bark Extract (ARBE) in RIRI. Methods: The chemical composition of ARBE was examined by LC-ESI-MS/MS. Network pharmacology was utilized to identify the RIRI molecular targets that could be aimed at by the identified major components of ARBE. Experimentally validated protein–protein interactions (PPIs) and compound-target networks were constructed using the STRING database and Cytoscape software. Molecular docking studies were employed to assess the interaction of the most relevant ARBE compounds with the hub RIRI-related targets. Furthermore, ARBE was tested in a rat model of RIRI. Results: The phytochemical analysis identified 95 components in ARBE, 37 of which were majors. Network analysis identified 312 molecular targets of RIRI that were associated with ARBE major compounds. Of these 312, the top targets in the experimentally validated PPI network were HSP90, EGFR, and P53. The most relevant compounds based on their peak area and network degree value included narcissoside, isorhamnetin-3-O-glucoside, and syringetin-3-O-glucoside, among others. Docking studies of the most relevant compounds revealed significant interactions with the top RIRI-related targets. In the in vivo RIRI experiments, pretreatment of ARBE improved kidney function and structural changes. ARBE reduced the renal expression of p-NfkB and cleaved caspase-3 by downregulating HSP90 and P53 in rats exposed to RIRI. Conclusion: Taken together, this study revealed the chemical composition of ARBE, depicted the interrelationship of the bioactive ingredients of ARBE with the RIRI-related molecular targets, and validated a nephroprotective effect of ARBE in RIRI.

Gut microbial sodium butyrate alleviates renal ischemia-reperfusion injury by regulating HES1/PPARα

This study investigated the effect of gut microbial sodium butyrate (NaB) on renal ischemia-reperfusion injury (IRI) and its mechanism using a rat model of renal IRI and a HK-2 cell model of hypoxia-reoxygenation (HR) injury. The activity of malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues and HK-2 cells was detected. ELISA was performed to measure the concentrations of TNF-α, IL-1β, and IL-6 in serum and cell culture supernatant. TUNEL staining and flow cytometry were used to assess apoptosis in kidney tissues and HK-2 cells, respectively. UCSC and JASPAR predicted the binding sites between HES1 and PPARα promoter, followed by experimental verification of the binding. NaB pretreatment inhibited oxidative stress, inflammation, and apoptosis following renal IRI in vivo and in vitro. NaB suppressed the expression of HES1 and promoted that of PPARα. Overexpression of HES1 or knockdown of PPARα in HR-treated HK-2 cells inhibited the protective effects of NaB. HES1 repressed the expression of PPARα by binding PPARα promoter. In conclusion, NaB may alleviate renal IRI by promoting the transcription of PPARα via downregulation of HES1.

Hsa Circ 001839 Promoted Inflammation in Renal Ischemia-Reperfusion Injury Through NLRP3 by miR-432-3p

Background: In recent years, increasing discovery of the extremely important regulatory effects of circular RNAs on biological development, angiogenesis, tumor genesis, and development, as well as stem cell proliferation and differentiation has provided new opportunities for investigating regulation mechanism in angiogenesis. Objectives: This study explored the expression of circ 001839 in renal ischemia-reperfusion injury (RI-RI) rats and whether its upstream microRNA-432-3p (miR-432-3p) affects inflammation in both RI-RI rats and NRK52E cells. Methods: Rat model of RI-RI was made, and circ 001839 was identified by the gene-chip analysis in RI-RI rats. Expression of circ 001839 and miR-432-3p was measured by reverse transcription-quantitative polymerase chain reaction, protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, IL-6, and IL-18 in rat serum and cell supernatant was determined by ELISA, and the expression of NOD-like receptor 3 (NLRP3) and other gap-associated proteins in NRK52E cells was evaluated by Western blot analysis. Next, to verify the regulatory relationship between circ 001839 and miR-432-3p, 2 luciferase reporters were constructed. Results: Circ 001839 expression of RI-RI rats and NRK52E cells was significantly upregulated, compared with the control group. Circ 001839 overexpression significantly increased inflammation through promoting TNF-α, IFN-γ, and IL-6 expression levels in NRK52E cells. Overexpression of miR-432-3p significantly promoted inflammation in NRK52E cells via induction of NLRP3. Moreover, miR-432-3p decreased the effects of circ 001839-induced inflammation in NRK52E cells. Conclusions: These findings suggested that circ 001839 promoted inflammation in RI-RI through NLRP3 by miR-432-3p.

PD22-04 ORAL ADMINISTRATION OF NANO-SIZED SILICON PARTICLES REGULATES GENE EXPRESSION RELATED TO OXIDATIVE STRESS AND SUPPRESSES RAT RENAL ISCHEMIA-REPERFUSION INJURY

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery I (PD22)1 Apr 2020PD22-04 ORAL ADMINISTRATION OF NANO-SIZED SILICON PARTICLES REGULATES GENE EXPRESSION RELATED TO OXIDATIVE STRESS AND SUPPRESSES RAT RENAL ISCHEMIA-REPERFUSION INJURY Masataka Kawamrua*, Ryoichi Imamura, Yuki Kobayashi, Ayumu Taniguchi, Shigeaki Nakazawa, Taigo Kato, Toyofumi Abe, Hikaru Kobayashi, and Norio Nonomura Masataka Kawamrua*Masataka Kawamrua* More articles by this author , Ryoichi ImamuraRyoichi Imamura More articles by this author , Yuki KobayashiYuki Kobayashi More articles by this author , Ayumu TaniguchiAyumu Taniguchi More articles by this author , Shigeaki NakazawaShigeaki Nakazawa More articles by this author , Taigo KatoTaigo Kato More articles by this author , Toyofumi AbeToyofumi Abe More articles by this author , Hikaru KobayashiHikaru Kobayashi More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000872.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Organ ischemia reperfusion injury (IRI) is unavoidable in kidney transplantation and induces reactive oxygen species and causes organ damage. Although the effectiveness of hydrogen for IRI has been reported for a long time, oral ingestion of hydrogen water and inhalation of hydrogen gas are difficult to apply widely in terms of efficiency and general use. We succeeded in generating a large amount of hydrogen by crushing silicon to nano-sized particle and reacting with water. A silicone component agent was administered to a rat model of renal IRI to examine whether renal injury could be suppressed. METHODS: Six-week-old male SD rats were administered a silicon component feed containing 1% nano-sized silicon particles and IRI surgery was performed one week later. This group was made into a silicon component group (IRI + Si group). An IRI group that administers normal diet and performs IRI surgery and a sham group that performs only right nephrectomy were prepared, and each group was compared 72 hours after surgery. RESULTS: Serum creatinine levels and urine protein significantly decreased in the IRI + Si group,compared to the IRI group. Serum malondialdehyde and urinary 8-hydroxydeoxyguanosine, which are oxidative stress markers, were also significantly decreased in the IRI + Si group. Transcriptome analysis by microarray showed that in the IRI + Si group, the expression of genes related to immune response, cytokine production, and apoptotic signal was decreased in comparison with the IRI group. Furthermore, suppression of mRNA expression level of inflammatory cytokines by quantitative PCR and reduction of renal tubular epithelial cell apoptosis by immunohistochemical evaluation were obtained, suggesting anti-inflammatory and anti-apoptotic effects. CONCLUSIONS: Rat renal IRI was suppressed by oral administration of nano-sized silicon particles, which is a novel hydrogen administration method. Source of Funding: This research was supported by Grants-in-aid for Scientific Research (18K16697) and Center of Innovation Science and Technology based Radical Innovation and Entrepreneurship Program (COI STREAM). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e460-e460 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masataka Kawamrua* More articles by this author Ryoichi Imamura More articles by this author Yuki Kobayashi More articles by this author Ayumu Taniguchi More articles by this author Shigeaki Nakazawa More articles by this author Taigo Kato More articles by this author Toyofumi Abe More articles by this author Hikaru Kobayashi More articles by this author Norio Nonomura More articles by this author Expand All Advertisement PDF downloadLoading ...

Identification of Hub Genes and Pathways in a Rat Model of Renal Ischemia-Reperfusion Injury Using Bioinformatics Analysis of the Gene Expression Omnibus (GEO) Dataset and Integration of Gene Expression Profiles.

BackgroundThis study aimed to identify hub genes and pathways in a rat model of renal ischemia-reperfusion injury (IRI) using bioinformatics analysis of the Gene Expression Omnibus (GEO) microarray dataset and integration of gene expression profiles.Material/MethodsGEO software and the GEO2R calculation method were used to analyze two mRNA profiles, including GSE 39548 and GSE 108195. The co-expression of differentially expressed genes (DEGs) were identified and searched in the DAVID and STRING databases for pathway and protein-protein interaction (PPI) analysis. Cytoscape was used to draw the PPI network. DEGs were also analyzed using the Molecular Complex Detection (MCODE) algorithm. Cytoscape and cytoHubba were used to analyze the hub genes and visualize the molecular interaction networks. Rats (n=20) included the IRI model group (n=10) and a control group (n=10). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure and compare the expression of the identified genes in rat renal tissue in the IRI model and the control group.ResultsTen hub genes were identified, STAT3, CD44, ITGAM, CCL2, TIMP1, MYC, THBS1, IGF1, SOCS3, and CD14. Apart from IGF1, qRT-PCR showed that expression of these genes was significantly increased in renal tissue in the rat model of IRI. The HIF-1α signaling pathway was involved in IRI in the rat model, which was supported by MCODE analysis.ConclusionsIn a rat model of renal IRI, bioinformatics analysis of the GEO dataset and integration of gene expression profiles identified involvement of HIF-1α signaling and the STAT3 hub gene.

Hypoxic Preconditioned Mesenchymal Stromal Cell Therapy in a Rat Model of Renal Ischemia-reperfusion Injury: Development of Optimal Protocol to Potentiate Therapeutic Efficacy.

Although previous and ongoing clinical studies have used stromal cells during renal ischemia-reperfusion injury (IRI), there is little consensus regarding the optimal protocol. We aimed to optimize the protocol for hypoxic preconditioned human bone marrow-derived mesenchymal stromal cell (HP-hBMSC) therapy in a rat model of renal IRI. We determined the optimal injection route (renal arterial, renal parenchymal, and tail venous injection), dose (low-dose: 1×106, moderate-dose: 2×106, and high-dose: 4×106), and injection period (pre-, concurrent-, and post-IRI). During optimal injection route study, renal arterial injections significantly reduced the decreasing glomerular filtration rate (GFR), as compared to GFRs for the IRI control group, 2 and 4 days after IRI. Therapeutic effects and histological recoveries were the greatest in the group receiving renal arterial injections. During the dose finding study, high-dose injections significantly reduced the decreasing GFR, as compared to GFRs for the IRI control group, 3 days after IRI. Therapeutic effects and histological recoveries were the greatest in the high-dose injection group. While determining the optimal injection timing study, concurrent-IRI injection reduced elevated serum creatinine levels, as compared to those of the IRI control group, 1 day after IRI. Pre-IRI injection significantly reduced the decreasing GFR, as compared with GFRs for the IRI control group, 1 day after IRI. Therapeutic effects and histological recoveries were the greatest in the concurrent-IRI group. In conclusion, the concurrent-IRI administration of a high dose of HP-hBMSC via the renal artery leads to an optimal recovery of renal function after renal IRI.

Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI.

Possible Protective Effect of Bone Marrow-Mesenchymal Stem Cells (BM-MSCs) Against the Remote Liver Injury Induced by Renal Ischemia Reperfusion in Male Albino Rats

Background: Renal ischemia-reperfusion injury (IRI) is a major cause of acute renal injury and leads to multiorgan dysfunction especially liver injury. Stem cell therapy has been used effectively in treatment of renal IRI. Aim of the work: To investigate the possible therapeutic effect of BM-MSC therapy on the remotely affected liver in a rat model of renal IRI and the mechanisms involved in this effect. Methods: Rats were divided into 3 groups; the sham-operated control group, the renal IRI group: bilateral renal IRI for 45 minutes followed by reperfusion, and BM-MSCs-injected group: rats were subjected to renal IRI and then received a single intravenous (iv) injection of BM-MSCs immediately after reperfusion. At the different time-points (days 1, 3, and 5) of the study, serum urea, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were estimated. Livers were removed and were divided: some specimens were homogenized for assessment of oxidant and antioxidant parameters, and other specimens were used for paraffin embedding for histological and immunohistochemical study. Results: Renal IRI resulted in a significant increase in serum levels of urea, creatinine, AST, ALT, and hepatic tissue levels of malondialdehyde (MDA) which attenuated on days 3 and 5 after BM-MSCs injection. MDA showed an early significant decrease in the BM-MSCs-injected group at day 1. Reduced glutathione (GSH) showed a significant decrease in the IRI sub-groups while BM-MSCs-injected sub-groups showed significantly higher levels of GSH on days 1, 3 and 5. Tissue sections showed that labeled BM-MSCs were engrafted into liver tissue. The IRI subgroups showed marked destruction of liver tissue e.g. disrupted lobular architecture, marked hepatocellular ballooning and cytoplasmic vaculations, and marked recruitment of the inflammatory cells with vascular congestion. While in the BM-MSCs-injected subgroups, there were gradual regeneration and restoration of lobular architecture, reduced degenerated cells, decreased congestion, and minimal inflammatory cell infiltration. By day 5, most hepatocytes had more or less normal appearance, arranged in cords with preserved general architecture and lacking evidence of major morphological injury. In addition, BM-MSCs significantly attenuated the liver immunohistochemical expression of tumor necrosis factor-alpha (TNF-α). Conclusion: BM-MSCs protects against the remote liver injury induced by renal IRI through early inhibition of inflammatory cell recruitment, inflammatory reactions, suppressing oxidative stress and lipid peroxidation, and rapid restoration of cellular and architectural integrity of the liver. This provides another important basis for the therapeutic concept of BM-MSCs in treatment of renal IRI by adding a beneficial effect on decreasing the remote liver injury besides considering it as a promising treatment in renal IRI.

Atorvastatin alleviates renal ischemia-reperfusion injury in rats by promoting M1-M2 transition.

Acute kidney injury (AKI) often occurs as a result of ischemia-reperfusion (IR). Previous studies have demonstrated that inflammation is an important contributor to AKI. Atorvastatin (ATO) possesses anti‑inflammatory properties and has been demonstrated to exert protective effects against renal IR injury (IRI). However, the underlying mechanism requires further study. In the present study, a rat model of renal IRI was successfully established. Consistent with the results of a previous study, ATO significantly attenuated IRI, which was supported by a decrease in serum creatinine and an increase in creatinine clearance rate, as well as alleviated pathological alterations in renal tubular cells. There are two types of activated macrophages: Proinflammatory M1 and anti‑inflammatory M2 macrophages, which have been demonstrated to exert contributory and protective effects on IRI, respectively. The present study demonstrated that treatment with ATO significantly decreased M1 macrophage density and increased M2 macrophage density, as compared with the IR group. In addition, it is well known that M1 macrophages can be induced by Thelper1 cytokines, including tumor necrosis factor (TNF)‑α and interferon (IFN)‑γ, whereas M2 macrophages can be induced by peroxisome proliferator-activated receptor (PPAR)‑γ. The present study indicated that ATO treatment significantly decreased the expression levels of TNF‑α and IFN‑γ, and increased PPAR‑γ expression. In conclusion, ATO may ameliorate renal IRI by promoting M1‑M2 transition. Furthermore, ATO‑mediated macrophage polarization in rats with renal IRI may be associated with the downregulation of TNF‑α and IFN‑γ, and the upregulation of PPAR-γ.

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

Background/Aims: Ischemia/reperfusion injury (IRI) plays a crucial role in renal transplantation and can cause renal failure associated with pyroptosis, a pro-inflammatory-induced programmed cell death. Small endogenous non-coding RNAs have been shown to be involved in renal ischemia/reperfusion injury. This study was performed to investigate which miRNAs regulate pyroptosis in response to renal ischemia/reperfusion injury and determine the mechanism underlying this regulation. Methods: An in vivo rat model of renal IRI was established, and the serum and kidneys were harvested 24 h after reperfusion to assess renal function and histological changes. For the in vitro study, the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia (5% CO₂, 1% O₂, and 94% N2) followed by 12 h of reoxygenation (5% CO₂, 21% O₂, and 74% N₂). The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Bioinformatics analyses were applied to predict miR-155 targets, which were then confirmed by a luciferase reporter assay. Results: We found that the levels of pyroptosis-related proteins, including caspase-1, caspase-11, IL-1β and IL-18, were significantly increased after renal ischemia/reperfusion injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in HK2 cells. Furthermore, our study revealed that miR-155 expression was substantially increased in the renal tissues of IRI rats and in HRI HK2 cells. Up-regulation of miR-155 promoted HK2 cell pyroptosis in HRI; conversely, knockdown of miR-155 attenuated this process. To understand the signaling mechanisms underlying the pro-pyroptotic activity of miR-155, we found that exogenous expression of miR-155 up-regulated the expression of caspase-1 as well as the pro-inflammatory cytokines IL-1β and IL-18. Moreover, miR-155 directly repressed FoxO3a expression and its downstream protein apoptosis repressor with caspase recruitment domain (ARC). Conclusions: Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.

Effect of Nigella sativa on ischemia-reperfusion induced rat kidney damage.

There are a few previously reported studies about the effect of Nigella sativa oil on renal ischemia-reperfusion injury (IRI). The aim of the present study was to test the hypothesis whether pre- or post-treatment with N. sativa hydroalcoholic extract (NSE) would reduce tissue injury and oxidative damages in a clinically relevant rat model of renal IRI. IRI was induced by clamping of bilateral renal arteries for 40 min fallowed by reperfusion for 180 min. NSE was prepared in a Soxhlet extractor and administrated with doses of 150 mg/kg or 300 mg/kg at 1 hr before ischemia induction (P-150 and 300) or at the beginning of reperfusion phase (T-150 and 300), via jugular catheter intravenously. The kidneys were then removed and subjected to biochemical analysis, comet assay or histopathological examination. The kidneys of untreated IRI rats had a higher histopathological score (P<0.001), while in P-150, as well as T-150 and T-300 groups tubular lesions significantly decreased (P<0.001). Pre- and post-treatment with NSE also resulted in a significant decrease in malondialdehyde (MDA) level (P<0.001) and DNA damage (P<0.001) that were increased by renal I/R injury. NSE treatment also significantly restore (P<0.01) the decrease in renal thiol content caused by IRI. The present study shows N. sativa extract has marked protective action against renal IRI, which may be partly due to its antioxidant effects.

Atrial natriuretic peptide attenuates kidney–lung crosstalk in kidney injury

BackgroundRenal ischemia–reperfusion injury (IRI) is a common cause of acute kidney injury after cardiovascular surgery, which in turn deteriorates oxygenation. Atrial natriuretic peptide (ANP) has natriuretic, diuretic, and anti-inflammatory effects. To elucidate whether renal IRI induces inflammation in the kidney and lung and ANP attenuates kidney–lung crosstalk. Materials and methodsThe rats were anesthetized, tracheostomized, mechanically ventilated, and randomized to four groups: saline + IRI (n = 12), ANP + IRI (n = 12), ANP + sham (n = 6), and saline + sham (n = 6). Saline (6 mL/kg/h) or ANP (0.2 μg/kg/min) at the rate of 6 mL/kg/h was started 5 min before clamping, respectively. Renal IRI was induced by clamping the left renal pedicle for 30 min. The hemodynamics, arterial blood gases, and plasma concentrations of creatinine and lactate were measured at baseline and 1, 2, and 3 h after declamping. Lung wet-to-dry ratio was measured. The mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL) 1β, and IL-6 and histologic localization of TNF-α in the kidney and lung were measured. ResultsRenal IRI induced metabolic acidosis, pulmonary edema, increases in plasma concentrations of creatinine and lactate, and augmentation of the cytokine mRNA expression and histologic localization of TNF-α in the kidney and Renal IRI induced lung. ANP prevented IRI-induced metabolic acidosis, pulmonary edema, increases in creatinine, lactate, and the cytokine mRNA expression, attenuated histologic localization of TNF-α in the kidney and lung, and increased oxygenation. ConclusionsANP has renoprotective and anti-inflammatory effects on the kidney and lung in a rat model of renal IRI, suggesting that ANP attenuates kidney–lung crosstalk.