Treatment Of Renal Ischemia-reperfusion Injury Research Articles

Hydrogen sulphide reduces renal ischemia-reperfusion injury by enhancing autophagy and reducing oxidative stress.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury. Hydrogen sulphide (H2S) exerts a protective effect in renal IRI. The present study was carried out to investigate the effects of exogenous H2S on renal IRI by regulating autophagy in mice. Mice were randomly assigned to control, IRI and NaHS (an H2S donor, 28, 56 and 100 μmol/kg) groups. Renal IRI was induced by clamping the bilateral renal pedicles with non-traumatic arterial clamp for 45 min and then reperfused for 24 h. Mice were administered intraperitoneally with NaHS 20 min prior to renal ischemia. Sham group mice underwent the same procedures without clamping. Serum and kidney tissues were harvested 24 h after reperfusion for functional, histological, oxidative stress, and autophagic determination. Compared with the control group, the concentrations of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), the protein levels of LC3II/I, Beclin-1 and P62, as well as the number of autophagosomes were significantly increased, but the activity of superoxide dismutase (SOD) was decreased after renal IRI. NaHS pre-treatment dramatically attenuated renal IRI-induced renal dysfunction, histological changes, MDA concentration and p62 expression in a dose-dependent manner. However, NaHS increased the SOD activity and the protein levels of LC3II/I and Beclin-1. These results indicate that exogenous H2S protects the kidney from IRI through enhancement of autophagy and reduction of oxidative stress. Novel H2S donors could be developed in the treatment of renal IRI.

Annexin-A5 monomer as a membrane repair agent for the treatment of renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is one of the causes of acute kidney injury. Annexin A5 (AnxA5), a calcium-dependent cell membrane-binding protein, shows protective effects in various organ IRI models. This study explored the therapeutic effect of exogenous AnxA5 monomer protein on renal IRI and its potential mechanism of action. Different doses of AnxA5 were injected intravenously to treat bilateral renal IRI in SD rats. This model confirmed the protective effects of AnxA5 on kidney structure and function. In vitro, HK-2 cells were subjected to hypoxia for 12h, followed by restoration of normal oxygen supply to simulate IRI. In vitro experiments demonstrated the mechanism of action of AnxA5 by measuring cellular activity and permeability. A comparison of the mutant AnxA5 protein M23 and the application of a calcium-free culture medium further validated the protective effect of AnxA5 by forming a network structure. Exogenous AnxA5 monomers prevented renal IRI by binding to the damaged renal tubular epithelial cell membrane, forming a two-dimensional network structure to maintain cell membrane integrity, and ultimately prevent cell death.

Ultrasmall Nanoparticles Regulate Immune Microenvironment by Activating IL-33/ST2 to Alleviate Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is a common disease with high morbidity and mortality. Renal IRI can cause the disorder of immune microenvironment and reprograming the immune microenvironment to alleviate excessive inflammatory response is crucial for its treatment. Cytokine IL-33 can improve the immune inflammatory microenvironment by modulating both innate and adaptive immune cells, and serve as an important target for modulating immune microenvironment of renal IRI. Herein, we report that bilobetin-functionalized ultrasmall Cu2- xSe nanoparticles (i.e., CSPB NPs) can activate the PKA/p-CREB/IL-33/ST2 signaling pathway to regulate innate and adaptive immune cells for reprograming the immune microenvironment of IRI-induced acute kidney injury. The biocompatible CSPB NPs can promote the polarization of M1-like macrophages into M2-like macrophages, and the expansion of ILC2 and Treg cells by activating IL-33/ST2 to modulate the excessive immune inflammatory response of renal IRI. More importantly, they can rapidly accumulate at the injured kidney to significantly alleviate IRI. This work demonstrates that modulating the expression of cytokines to reprogram immune microenvironment has great potential in the treatment of renal IRI and other ischemic diseases.

Theaflavin pretreatment ameliorates renal ischemia/reperfusion injury by attenuating apoptosis and oxidative stress in vivo and in vitro

Oxidative stress-induced apoptosis is an important pathological process in renal ischemia/reperfusion injury (RIRI). Theaflavin (TF) is the main active pigment and polyphenol in black tea. It has been widely reported because of its biological activity that can reduce oxidative stress and protect against many diseases. Here, we explored the role of theaflavin in the pathological process of RIRI. In the present study, the RIRI model of 45 min ischemia and 24 h reperfusion was established in C57BL/6 J male mice, and theaflavin was used as an intervention. Compared with the RIRI group, the renal filtration function, renal tissue damage and antioxidant capacity of the theaflavin intervention group were significantly improved, while the level of apoptosis was reduced. TCMK-1 cells were incubated under hypoxia for 48 h and then reoxygenated for 6 h to simulate RIRI in vitro. The application of theaflavin significantly promoted the translocation of p53 from cytoplasm to nucleus, upregulated the expression of glutathione peroxidase 1 (GPx-1) in cells, and inhibited oxidative stress damage and apoptosis. Transfection with p53 siRNA can partially inhibit the effect of theaflavin. Thus, theaflavin exerted a protective effect against RIRI by inhibiting apoptosis and oxidative stress via regulating the p53/GPx-1 pathway. We conclude that theaflavin has the potential to become a candidate drug for the prevention and treatment of RIRI.

Molecular mechanism of NR4A1/MDM2/P53 signaling pathway regulation inducing ferroptosis in renal tubular epithelial cells involved in the progression of renal ischemia-reperfusion injury

Revealing the possible molecular mechanism of the NR4A1 (nuclear receptor subfamily 4 group A member 1)-MDM2 (MDM2 proto-oncogene)-P53 (tumor protein p53) signaling pathway that induces ferroptosis in renal tubular epithelial cells. Renal ischemia-reperfusion injury (RIRI) -related datasets were obtained from the GEO database. Differentially expressed genes in RIRI were analyzed using R language, intersected with RIRI-related genes in the GeneCard database, and retrieved from the literature to finally obtain differential ferroptosis-related genes. An in vitro cell model of RIRI was constructed using mouse renal cortical proximal tubule epithelial cells (mRTEC cells) treated with hypoxia-reoxygenation (H/R). Bioinformatic analysis showed that NR4A1 may be involved in RIRI through the induction of ferroptosis; in addition, we predicted through online databases that the downstream target gene of NR4A1, MDM2, could be targeted and regulated by ChIP and dual luciferase assays, and that NR4A1 could prevent MDM2 by inhibiting it, and NR4A1 was able to promote ferroptosis by inhibiting the ubiquitinated degradation of P53. NR4A1 expression was significantly increased in mRTEC cells in the hypoxia/reoxygenation model, and the expression of ferroptosis-related genes was increased in vitro experiments. NR4A1 reduces the ubiquitinated degradation of P53 by targeting the inhibition of MDM2 expression, thereby inducing ferroptosis and ultimately exacerbating RIRI by affecting the oxidative respiration process in mitochondria and producing oxidized lipids. This study presents a novel therapeutic approach for the clinical treatment of renal ischemia-reperfusion injury by developing drugs that inhibit NR4A1 to alleviate kidney damage caused by renal ischemia-reperfusion.

Gene signature and prediction model of the mitophagy-associated immune microenvironment in renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is an inevitable occurrence during kidney transplantation. Mitophagy, ferroptosis, and the associated immune microenvironment (IME) have been shown to play important roles in renal IRI. However, the role of mitophagy-associated IME genes in IRI remains unclear. In this study, we aimed to construct a prediction model of IRI prognosis based on mitophagy-associated IME genes. The specific biological characteristics of the mitophagy-associated IME gene signature were comprehensively analyzed using public databases such as GEO, Pathway Unification, and FerrDb. Correlations between the expression of prognostic genes and immune-related genes and IRI prognosis were determined by Cox regression, LASSO analysis, and Pearson's correlation. Molecular validation was performed using human kidney 2 (HK2) cells and culture supernatant as well as the serum and kidney tissues of mice after renal IRI. Gene expression was measured by PCR, and inflammatory cell infiltration was examined by ELISA and mass cytometry. Renal tissue damage was characterized using renal tissue homogenate and tissue sections. The expression of the mitophagy-associated IME gene signature was significantly correlated with IRI prognosis. Excessive mitophagy and extensive immune infiltration were the primary factors affecting IRI. In particular, FUNDC1, SQSTM1, UBB, UBC, KLF2, CDKN1A, and GDF15 were the key influencing factors. In addition, B cells, neutrophils, T cells, and M1 macrophages were the key immune cells present in the IME after IRI. A prediction model for IRI prognosis was constructed based on the key factors associated with the mitophagy IME. Validation experiments in cells and mice indicated that the prediction model was reliable and applicable. We clarified the relationship between the mitophagy-related IME and IRI. The IRI prognostic prediction model based on the mitophagy-associated IME gene signature provides novel insights on the prognosis and treatment of renal IRI.

Effect of methyl eugenol on hypoxia/reoxygenation injury of human renal tubular epithelial cells and its mechanism

This study aimed to investigate the effect of methyl eugenol(ME) on hypoxia/reoxygenation(H/R)-induced injury of human renal tubular epithelial HK-2 cells and its mechanism. The viability of HK-2 cells cultured with different concentrations of ME and exposed to H/R was detected by cell counting kit-8(CCK-8) assay. The effect of ME on the morphology of HK-2 cells was observed under an inverted microscope. The content of intracellular reactive oxygen species in different groups was detected after 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA) fluorescence staining. Cell apoptosis was determined by flow cytometry. Changes in mitochondrial membrane potential were monitored by JC-1 dye. The concentrations of nuclear factor erythroid 2 related factor 2(Nrf2), heme oxygenase-1(HO-1), and nicotinamide adenine dinucleotide phosphatase oxidase 4(Nox4) were measured by Western blot, followed by the assay of Nrf2 concentration changes in cytoplasm and nucleus by confocal fluorescence staining. The results showed that when the concentration of ME was 0-40 μmol·L~(-1), the activity of HK-2 cells was not affected. Compared with the model group, ME enhanced the activity of HK-2 cells and the cell morphology was normal. As revealed by further experiments, ME inhibited the release of reactive oxygen species and the decline in mitochondrial membrane potential of HK-2 cells after H/R injury, promoted Nrf2/HO-1 expression and Nrf2 translocation to the nucleus, and down-regulated the expression of Nox4, thereby significantly reducing apoptosis. This protective effect of ME could be reversed by the specific Nrf2 inhibitor ML385. These findings have preliminarily proved that ME effectively protected HK-2 cells against H/R injury, which might be related to its promotion of Nrf2/HO-1 signaling pathway and inhibition of Nox4. Such exploration on the possible mechanism of ME in the treatment of renal ischemia-reperfusion injury(IRI) and protection of organ function from the perspective of antioxidant stress has provided reference for related research on the treatment of acute kidney injury with traditional Chinese medicine.

The efficiency of oxerutin on apoptosis and kidney function in rats with renal ischemia reperfusion injury.

Background: Renal ischemia-reperfusion injury (RIRI) is the most frequent cause of acute renal failure in clinical conditions such as trauma and shock as well as renal surgeries. Oxerutin is a member of the flavonoid family and possesses antioxidant properties. The aim of this study was to investigate whether oxerutin has protective effects on RIRI. Twenty-eight male Wistar albino rats were randomly divided into three groups: sham control group (n=8), RIRI group (n=10), and RIRI + oxerutin group (n=10). RIRI was achieved by clamping the left renal artery for 30 min, followed 1-h reperfusion period. Thereafter, blood samples and left kidney tissue samples were taken for histopathological and biochemical examination. Blood urea nitrogen (BUN), urea, creatinine, and cystatin C levels, which are indicators of kidney function, as well as tumor necrosis factor-alpha, which is an indicator of inflammation were analyzed in blood samples. Total antioxidant status and total oxidant status (TOS), which are indicators of oxidative stress were analyzed on renal tissues. The apoptotic index, an indicator of kidney damage, as well as histopathological changes were evaluated on renal tissues. The apoptotic index, TOS, tumor necrosis factor-alpha, BUN, and urea levels were lower in the RIRI + oxerutin group than in the RIRI group (p<0.05). The results demonstrated that the histopathological and biochemical properties of oxerutin protected rats from RIRI. The findings obtained in this study show that prophylactic administration of oxerutin has protective effects on apoptosis and renal failure caused by RIRI. Therefore, oxerutin can be used as an effective prophylactic agent in the treatment of RIRI.

VASPIN reduces inflammation and endoplasmic reticulum stress of renal tubular epithelial cells by inhibiting HMGB1 and relieves renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is a clinically common issue and the resulting acute kidney injury (AKI) seriously threatens the patient's life. Therefore, prevention and treatment of renal IRI are the key to alleviating AKI in such patients. The purpose of this study was to explore the effects of VASPIN on mouse renal IRI and human renal proximal tubular epithelial cells (HK-2 cells) to provide a new direction for the treatment of clinical renal IRI. C57/BL6 mice were used to construct a renal IRI model and recombinant mouse VASPIN was subcutaneously injected to determine whether VASPIN can alleviate renal IRI in mice by histological examination and detection of mouse urine and serum related indicators. In addition, HK-2 cells were cultured and an IRI model was constructed at the cellular level by hypoxia reoxygenation to examine the effect and mechanism of VASPIN on endoplasmic reticulum stress (ERS) in HK-2 cells. Results revealed that in VASPIN-treated mice, edema of renal tubular epithelial cells was significantly improved and renal injury markers netrin-1 and L-FAPB were decreased in urine. In addition, VASPIN also reduced the expression of inflammatory factors in mouse serum and the level of oxidative stress in kidney tissue. The expression of ERS-related molecules (GRP78, ATF6, caspase12, and CHOP) in HK-2 cells treated with VASPIN was significantly reduced and VASPIN decreased the expression of the pro-inflammatory factor HMGB1. Moreover, VASPIN promoted the activity of the Nrf2/ARE/HO-1 signaling pathway and inhibited the NF-кB signaling pathway by inhibiting HMGB1. VASPIN reduces inflammation and ERS levels in kidney tissue and attenuates renal IRI by activating the Nrf2/ARE/HO-1 signaling pathway and inhibiting the NF-кB signaling pathway via inhibition of HMGB1.

Kidney extracellular matrix hydrogel enhances therapeutic potential of adipose-derived mesenchymal stem cells for renal ischemia reperfusion injury

Stem cell-based therapy has been suggested as a promising option for the treatment of renal ischemia-reperfusion injury (IRI). However, how to efficiently deliver stem cells remains a challenge. In the present study, we firstly proposed the utilization of kidney extracellular matrix hydrogel (ECMH) as an injectable scaffold for delivering adipose-derived mesenchymal stem cells (ad-MSCs) into ischemic kidneys. A modified strategy of decellularization and gelation was introduced to prepare the ECMH, by which the bioactive ingredients were retained as much as possible. Bioluminescence living imaging and immunofluorescence revealed that ECMH could significantly elevate the retention and survival rate of transplanted ad-MSCs in damaged kidneys and reduce their escape rate to other organs, which consequently resulted to the enhanced therapeutic effect of ad-MSCs on renal IRI. Further, in vitro evidence demonstrated that ECMH could remarkably reduce the oxidative stress and apoptosis, promote the proliferation, secretion, and epithelial differentiation of ad-MSCs, as well as facilitate cell migration while acting as a sustained-release scaffold. This study establishes an effective approach to enhance the therapeutic potential of ad-MSCs for renal IRI. Our findings suggest that ECMH derived from organs or tissues would be a promising injectable scaffold for stem cell-based therapy. Statement of significanceIt remains a challenge to efficiently deliver stem cells to target tissues, which may limit the clinical application of stem cell-based therapy. In this study, we developed a modified strategy of decellularization and gelation to prepare the kidney extracellular matrix hydrogel (ECMH). In vivo and in vitro evidence indicated that the kidney ECMH could improve the retention and survival rate, as well as multiple biological functions of adipose-derived mesenchymal stem cells, thereby contributing to the histological and functional recovery of injured kidneys induced by ischemia-reperfusion. Our findings highlight the use of organs or tissues derived ECMH as a promising stem cell delivery scaffold for tissue repair.

Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation.

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

Identification of Candidate Genes Involved in Renal Ischemia/Reperfusion Injury.

Renal ischemia/reperfusion injury (IRI) is a main risk factor for the occurrence of delayed graft function or primary graft nonfunction of kidney transplantation. However, it lacks ideal molecular markers for indicating IRI in kidney transplantation. The present study is to explore novel candidate genes involved in renal IRI. Experimental renal IRI mouse models were constructed, and the differentially expressed genes were screened using a microarray assay. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed. The expression of genes was detected using real-time qPCR assay. Western blotting and immunohistochemistry staining assays were performed for protein determination. We identified that renal IRI induced the upregulation of SPRR2F, SPRR1A, MMP-10, and long noncoding RNA (lncRNA) Malat1 in kidney tissues for 479.3-, 4.98-, 238.1-, and 3.79-fold, respectively. The expression of miR-139-5p in kidney tissues of IRI-treated mice was decreased to 40.4% compared with the sham-operated mice. These genes are associated with keratinocyte differentiation, regeneration and repair of kidney tissues, extracellular matrix degradation and remodeling, inflammation, and cell proliferation in renal IRI. Identification of novel biomarkers involved in renal IRI may provide evidences for the diagnosis and treatment of renal IRI.

Renoprotective effects of dexmedetomidine against ischemia-reperfusion injury in streptozotocin-induced diabetic rats.

BackgroundDiabetic patients are susceptible to renal ischemia-reperfusion injury, which leads to perioperative complications. Activation of NOD-like receptor protein 3 (NLRP3) inflammasome participates in the development of diabetes, and contributes to renal ischemia-reperfusion injury. Dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist, shows renoprotective effects against ischemia-reperfusion injury. We aimed to elucidate the effects, underlying mechanisms, and optimal timing of DEX treatment in diabetic rats.MethodsMale Sprague-Dawley rats (n = 12 per group) were randomly divided into normal-sham, diabetes-sham, diabetes-ischemia-reperfusion-control, diabetes-ischemia-reperfusion-DEX-pre-treatment, and diabetes-ischemia-reperfusion-DEX-post-treatment groups. Renal ischemia-reperfusion injury was induced in diabetic rats by occlusion of both renal arteries for 45 min, followed by reperfusion for 24 h. DEX (10 μg/kg) was administered intraperitoneally 1 h before ischemia (pre-treatment) or upon reperfusion (post-treatment). After reperfusion, renal tissue was biochemically and histopathologically evaluated.ResultsDEX treatment attenuated ischemia reperfusion-induced increase in NLRP3, caspase-1, IL-1β, phospho-AKT, and phospho-ERK signaling. Moreover, oxidative stress injury, inflammatory reactions, apoptosis, and renal tubular damage were favorably modulated by DEX treatment. Furthermore, post-reperfusion treatment with DEX was significantly more effective than pre-treatment in modulating NLRP3 inflammasome, AKT and ERK signaling, and oxidative stress.ConclusionsThis study shows that the protective effects of DEX in renal ischemia-reperfusion injury are preserved in diabetic conditions and may potentially provide a basis for the use of DEX in clinical treatment of renal ischemia-reperfusion injury.

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.

Rutaecarpine alleviates renal ischemia reperfusion injury in rats by suppressing the JNK/p38 MAPK signaling pathway and interfering with the oxidative stress response.

In the present study, the protective effect and the potential underlying mechanism of rutaecarpine (Ru) on renal ischemia reperfusion injury (IRI) in rats were investigated. A renal ischemia reperfusion mouse model was established. Ru at 30, 60mg/kg administered intraperitoneally prior to reperfusion led to attenuated renal injury. The results demonstrated that Ru treatment significantly reduced the content of serum creatinine, urea nitrogen and neutrophil gelatinase‑associated lipocalin in rats with renal IRI. In addition, Ru treatment improved the degree of renal proximal tubular necrosis, decreased the content of inflammatory cytokines in reperfused renal tissue and increased serum superoxide dismutase levels to protect the kidney. The associated underlying mechanism may involve the inhibition of p38 kinase phosphorylation and c‑Jun N‑terminal kinase, anti‑lipid peroxidation, elimination of free radicals, and a reduction in the degree of apoptotic damage and oxidative stress injury induced by renal IRI. Therefore, Ru may be a suitable compound for the prevention and treatment of renal IRI.

Research progress of p38MAPK signaling pathway in renal ischemia reperfusion injury

Renal ischemia reperfusion injury, a common pathological process in kidney operation, is always seen in extracorporeal shock wave lithotripsy and renal transplantation, and even the main reason leading to acute kidney injury. The pathogenesis of renal ischemia reperfusion injury (RIRI) is complex so that we have not found better drugs in clinical to prevent and treat it. P38 signaling pathway activation is one of the important mechanisms leading to renal ischemia reperfusion injury. This article reviewed the main functions of P38 mitogen activated protein kinases (P38MAPK) signaling pathway and its role in RIRI in order to provide a new idea for the prevention and treatment of RIRI. Key words: p38 mitogen-activated protein kinases/ME; Signal transduction; Reperfusion injury/ME; Kidney diseases/ME; Ischemia; Review

Does protocatechuic acid, a natural antioxidant, reduce renal ischemia reperfusion injury in rats?

Protocatechuic acid (PCA), which has antioxidant property, is a simple phenolic compound commonly found in many plants, vegetables, and fruits, notably in green tea and almonds. Present study was an investigation of the effects of PCA on rat kidney with ischemia/reperfusion (IR) injury. Sprague-Dawley rats were randomly divided into 4 groups: (1) Sham, (2) Renal IR, (3) Renal IR+Vehicle, and (4) Renal IR+PCA. Renal reperfusion injury was induced by clamping renal pedicle for 45 minutes after right nephrectomy was performed, followed by reperfusion for 3 hours. Dose of 80 mg/kg PCA was intraperitoneally administered to 1 group immediately before renal ischemia; 33% polyethylene glycol was used as vehicle. Total antioxidant status (TAS), malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), and interleukin-6 levels were measured in blood and kidney tissue samples taken from sacrificed rats. Kidney tissue samples were examined and scored histopathologically. Terminal deoxynucleotidyltransferase-mediated dUTP digoxigenin nick end labeling assay method was used to detect apoptotic cells. It was found that PCA significantly reduced serum MDA, TNF-α, and kidney MDA levels, while it increased serum and kidney TAS and SOD levels. Histopathological scores were significantly higher for the group given PCA. PCA reduced oxidative stress and can be used as an effective agent in treatment of renal IR injury.

Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice.

Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) have been studied in several models of immune-mediated disease because of their unique immunomodulatory properties. We hypothesized that HUCB-MSCs could suppress the inflammatory response in postischemic kidneys and attenuate early renal injury. In 8- to 10-wk-old male C57BL/6 mice, bilateral ischemia-reperfusion injury (IRI) surgery was performed, and 1 × 10(6) HUCB-MSCs were injected intraperitoneally 24 h before surgery and during reperfusion. Renal functional and histological changes, HUCB-MSC trafficking, leukocyte infiltration, and cytokine expression were analyzed. Renal functional decline and tubular injury after IRI were attenuated by HUCB-MSC treatment. PKH-26-labeled HUCB-MSCs trafficked into the postischemic kidney. Although numbers of CD45-positive leukocytes in the postischemic kidney were comparable between groups, the expression of interferon-γ in the postischemic kidney was suppressed by HUCB-MSC treatment. The rapid decrease in intrarenal VEGF after IRI was markedly mitigated by HUCB-MSC treatment. In inflammatory conditions simulated in a cell culture experiment, VEGF secretion from HUCB-MSCs was substantially enhanced. VEGF inhibitor abolished the renoprotective effect of HUCB-MSCs after IRI. Flow cytometry analysis revealed the decreased infiltration of natural killer T cells and increased number of regulatory T cells in postischemic kidneys. In addition, these effects of HUCB-MSCs on kidney infiltrating mononuclear cells after IRI were attenuated by VEGF inhibitor. HUCB-MSCs attenuated renal injury in mice in the early injury phase after IRI, mainly by humoral effects and secretion of VEGF. Our results suggest a promising role for HUCB-MSCs in the treatment of renal IRI.

Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.

Distant organ injury following acute kidney injury

(AKI) is associated with unacceptablyhigh mortality that can range from 40 to 60% in some cases(14). The incidence of AKI continues to increase (15, 16) andis associated with a changing spectrum of illnesses, significantcomorbidandextrarenalcomplications(12),andunsatisfactorypreventive or treatment strategies (5). The etiology of AKI isdiverse, and ischemia constitutes the major cause of thiscondition. Ischemic AKI is a dynamic process that oftencoexists with multiple organ failure and involves hemody-namic alteration, inflammation, and direct injury to the tubularepithelium (9). Interestingly, renal failure per se usually is notthe cause of death in AKI (7), but rather both cardiogenic (2,10) and noncardiogenic acute lung injury (ALI) (13) accountfor the high mortality associated with AKI. These comorbidconditions can explain the failed treatment regimens, espe-cially when mortality is used as a clinical trial end point.Currently, the mortality of combined AKI and ALI is ex-tremely high and may approach 80% (11). Therefore, definingthe mechanism by which AKI causes ALI is important if weare to be successful in reducing overall mortality associatedwith AKI. Experimental studies demonstrated increased pul-monary vascular permeability, lung edema, alveolar hemor-rhage, and leukocyte trafficking following ischemic AKI (1, 6,8). The recent work of Hoke et al. (4) has shed new light on therole of the kidney in lung injury. In their study, they sought todetermine the the effect of an acute cessation of kidneyfunctiononlunginjury.Theabsenceofclearancewasachievedby either bilateral nephrectomies or by bilateral renal pedicleclamps. The latter method using bilateral pedicles clamp for 22min was associated with effects related to ischemia-reperfusion.AKI induced by ischemia-reperfusion or bilateral nephrectomywas associated with a change in level and pattern of serumcytokines. However, lung injury was similar following renalischemia-reperfusion or bilateral nephrectomies. These resultssuggest that the absence of kidneys results in lung injuryindependent of ischemia-reperfusion. By inference, these re-sults indicate a potentially important role that the kidneys playin maintaining serum cytokine balance and pulmonary ho-meostasis.In this issue of the