Acute Renal Ischemia-reperfusion Injury Research Articles

Технические особенности экспериментальной модели острого ишемически-реперфузионного повреждения почек

Технические особенности экспериментальной модели острого ишемически-реперфузионного повреждения почек

Protective effect of baicalein on renal ischemia/reperfusion injury in the rat

Objective: To investigate the protective effect and the mechanism of baicalein (Bai) in rats with renal ischemia–reperfusion injury (RIRI). Methods: Twenty-four male Sprague–Dawley rats were divided into three groups: sham, IR, and IR + Bai. Bai was administered by tail vein injection (30 mg/kg) 30 min before reperfusion in the IR + Bai group. The IR group and sham group received saline vehicle via the intravenous route. Results: Rats that underwent RIRI exhibited renal functional impairment, histological changes, significantly increased advanced oxidation protein product (AOPP) and malondialdehyde (MDA) levels (p < 0.01), and ICAM-1 and MCP-1 protein and mRNA expression were significantly upregulated (p < 0.01). Administration of Bai reduced AOPP and MDA levels, significantly inhibited expression of inflammatory factors (p < 0.05), and markedly improved renal function. Conclusion: Bai promotes the recovery of renal function in established acute RIRI, and alleviates kidney injury in a rat model.

Atorvastatin preconditioning protect renal function against ischemia-reperfusion injury by increasing expression of endothelial nitric oxide synthase

Objective To investigate the protective effect of atorvastatin (ATO) preconditioning on rats with acute renal ischemia-reperfusion (I/R) injury and its effect on endothelial nitric oxide synthase (eNOS).Methods 18 male Sprague Dawley rat was randomly distributed into three groups:sham,I/R and I/R + ATO.ATO was given by intraperitoneal injection [20 mg/(kg·d)] 2 weeks before ischemia/ reperfusion operation in the I/R + ATO group.The sham group and I/R group received saline vehicle via the intraperitoneal route.Serum levels of blood urea nitrogen (BUN),creatinine (Cr),nitric oxide (NO) and expression levels of myeloperoxidase (MPO),eNOS and superoxide dismutase (SOD) in renal tissue were analyzed.Results Comparing with the sham group,ATO treatment reduced the elevation of BUN (mmol/L) (78.59±10.47 vs.128.54 ±6.69) andCr(μmol/L) (19.44±9.3vs.31.44±9.87) level,inhibited the expression of MPO (U/g) (1.25 ±0.14 vs.1.68 ±0.12),but increased the expression of SOD [U/(mg·pro)] (139 ± 10.6 vs.109 ±4.7),and enhance the elevation of NO (μmol/L)(94.65 ± 10.33 vs.67.50 ±8.32) and eNOS.All differences were significant.(P ＜0.01).Conclusion These data suggest that ATO protect renal function from ischemia-reperfusion injury probably by promote the expression of eNOS and consequently increase the production of NO. Key words: Atorvastatin preconditioning; Ischemia/reperfusion; Endothelial nitric oxide synthase; Nitric oxide

Les lésions musculaires. Diagnostic, évolution et traitement médical et paramédical

Ischemia reperfusion injury (IRI) is a common complication after kidney transplantation. Peptide GV1001 is a peptide vaccine representing a 16−amino acid human telomerase reverse transcriptase sequence, which has been reported to possess potential antineoplastic and anti-inflammatory activity. This study aimed to investigate the potential effects of peptide GV1001 on renal IRI.Peptide GV1001 was subcutaneously administered to C57BL6/J mice 30 minutes before and 12 hours after bilateral IRI. Sham operation and phosphate-buffered saline (PBS) injection were used as controls. Blood and renal tissues were harvested at 1 day after IRI.Peptide GV1001 treatment significantly attenuated renal functional deterioration after IRI (peptide GV1001 group vs PBS group; blood urea nitrogen, P < .05; creatinine, P < .05). Peptide GV1001 treatment also attenuated renal tissue injury (tubular injury score; the peptide GV1001 group vs PBS group; P < .001). Renal apoptosis was also lower in the peptide GV1001 group. Immunohistochemical studies showed that IRI increased perirenal infiltration of both neutrophils and macrophages, and that peptide GV1001 significantly attenuated this process. Expression of interleukin-6 and monocyte chemotactic protein-1 was significantly reduced by peptide GV1001 treatment.Peptide GV1001 ameliorates acute renal IRI by reducing inflammation and apoptosis; therefore, it is promising as a potential therapeutic agent for renal IRI. The mechanisms of protection should be explored in further studies.

Microparticles from Kidney-Derived Mesenchymal Stem Cells Act as Carriers of Proangiogenic Signals and Contribute to Recovery from Acute Kidney Injury

We recently demonstrated the use of in vitro expanded kidney-derived mesenchymal stem cells (KMSC) protected peritubular capillary endothelial cells in acute renal ischemia-reperfusion injury. Herein, we isolated and characterized microparticles (MPs) from KMSC. We investigated their in vitro biologic effects on human endothelial cells and in vivo renoprotective effects in acute ischemia-reperfusion renal injury. MPs were isolated from the supernatants of KMSC cultured in anoxic conditions in serum-deprived media for 24 hours. KMSC-derived MPs demonstrated the presence of several adhesion molecules normally expressed on KMSC membranes, such as CD29, CD44, CD73, α4, 5, and 6 integrins. Quantitative real time PCR confirmed the presence of 3 splicing variants of VEGF-A (120, 164, 188), bFGF and IGF-1 in isolated MPs. MPs labeled with PKH26 red fluorescence dye were incorporated by cultured human umbilical vein endothelial cells (HUVEC) via surface molecules such as CD44, CD29, and α4, 5, and 6 integrins. MP dose dependently improved in vitro HUVEC proliferation and promoted endothelial tube formation on growth factor reduced Matrigel. Moreover, apoptosis of human microvascular endothelial cell was inhibited by MPs. Administration of KMSC-derived MPs into mice with acute renal ischemia was followed by selective engraftment in ischemic kidneys and significant improvement in renal function. This was achieved by improving proliferation, of peritubular capillary endothelial cell and amelioration of peritubular microvascular rarefaction. Our results support the hypothesis that KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischemic kidneys.

Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury

Exacerbated inflammation in renal ischemia–reperfusion injury, the major cause of intrinsic acute renal failure, is a key trigger of kidney damage. During disease endogenous danger signals stimulate innate immune cells via Toll-like receptors (TLR)-2 and -4 and accelerate inflammatory responses. Here we show that production of soluble biglycan, a small leucine-rich proteoglycan, is induced during reperfusion and that it functions as endogenous agonist of TLR-2/4. Biglycan-mediated activation of TLR-2/4 initiates an inflammatory response in native kidneys, which is marked by the release of cytokines and chemokines and recruitment of inflammatory cells. Overexpression of soluble circulating biglycan before ischemic reperfusion enhanced plasma and renal levels of TNF-α, CXCL1, CCL2 and CCL5, caused influx of neutrophils, macrophages and T cells and overall worsened renal function in wild type mice. We provide robust genetic evidence for TLR-2/4 requirement insofar as biglycan biological effects were markedly dampened in mice deficient in both innate immune receptors, Tlr2−/−;Tlr4−/− mice. Thus, signaling of soluble biglycan via TLR-2/4 could represent a novel therapeutic target for the prevention and possible treatment of patients with acute renal ischemia–reperfusion injury.

Preconditioning With Gabexate Is Superior to Inosine for Ameliorating Acute Renal Ischemia-Reperfusion Injury in Rats

ObjectiveThe objective of this study was to compare the protease inhibitor gabexate with widely used inosine for reducing renal ischemia-reperfusion injury. MethodA total of 48 rats were divided into 4 groups of 12 and administered gabexate, inosine, normal saline (NS), or nothing by injection through the vena dorsalis of the penis. Then all rats were subjected to right nephrectomy and 30-minute warm ischemia of the left kidney. At 24 and 48 hours after reperfusion, blood samples were collected from the inferior vena cava and serum creatinine (SCr) was assayed. Left kidney tissue was homogenized and used to assay malondialdehyde (MDA) and superoxide dismutase (SOD). The tissue was also analyzed using hematoxylin-eosin (HE) staining, TUNEL staining, and NF-κB immunohistochemistry. ResultsSCr level decreased after reperfusion more in the gabexate group than in the other groups. Reperfused kidney tissue in the gabexate group showed lower MDA levels but higher SOD activity than did tissue in the inosine and saline groups, as well as lower pathology scores based on HE staining, lower necrosis index, and lower levels of NF-κB expression (all P < .05). Tissue in the inosine and saline groups showed similar necrosis index and NF-κB expression (P > .05). ConclusionPreconditioning with gabexate is superior to preconditioning with inosine for ameliorating rat renal ischemia-reperfusion injury. Future studies are needed to verify the effects of gabexate in the clinic, especially for kidney transplantation.

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe(2+)), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe(2+) 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe(2+) increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe(2+) treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe(2+) group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe(2+)-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe(2+) can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.

The Renoprotective Effect of Bone Marrow-Derived Endothelial Progenitor Cell Transplantation on Acute Ischemia-Reperfusion Injury in Rats

ObjectiveTo investigate the renoprotective effects of exogenous endothelial progenitor cells (EPCs) on acute renal ischemia-reperfusion (I/R) injury in rats. MethodsEPCs were collected by in vitro culture of mononuclear cells derived from rat bone marrow. The EPC labeling was performed using chloromethyl-benzamidodialkylcarbocyanine (CM-Dil). Sprague-Dawley rats were equally randomized into an I/R, an EPC, and a control group. We evaluated blood urea nitrogen (BUN) and serum creatinine (Scr), kidney morphology, apoptosis and microvessel density. EPC homing into I/R injured kidneys was observed using a fluorescence microscope. ResultsAfter EPC transplantation, CM-Dil-labeled EPCs were noted at the corticomedullary junction of injured kidneys. The levels of BUN and Scr were markedly lower among the EPC than the I/R group (P < .05). The histopathologic score was higher in the I/R than the EPC group (P < .05). Apoptosis of tubular epithelial cells was substantially reduced among EPC-treated rats (P < .01). In addition, more CD34+ microvessels were documented among the EPC than the other two groups (P < .01). The expression levels of vascular endothelial growth factor (VEGF) were also increased greatly in the EPC group (P < .05). ConclusionTransplanted exogenous EPCs exert protective effects on renal function by maintaining the integrity of peritubular capillaries after I/R injury.

Low molecular weight fucoidan against renal ischemia‐reperfusion injury via inhibition of the MAPK signaling pathway

Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) in both native and transplanted kidneys. As a common pathophysilological cause of acute renal failure (ARF), IRI‐induced AKI occurs in many clinical settings including renal transplantation, shock, and vascular surgery. The objective of the present study was to evaluate whether low‐molecular‐weight fucoidan (LMWF) could attenuate renal IRI in an animal model and in vitro cell models and study the mechanisms in which LMWF protects from IRI. Male mice were subjected to right renal ischemia for 30 min and reperfusion for 24 h, or to a sham operation with left kidney removed. Kidneys undergone IR showed characteristic morphological changes, such as tubular dilatation, and brush border loss. However, LMWF significantly corrected the renal dysfunction and the abnormal levels of MPO, MDA and SOD induced by IR. LMWF also inhibited the activation of MAPK pathways, which consequently resulted in a significant decrease in the expression of cyto‐c, ratios of Bax/Bcl‐2 and cleaved caspase‐3/caspase‐3, and phosphorylation of p53. LMWF alleviated hypoxia‐reoxygenation or CoCl2 induced cell viability loss and ΔΨm dissipation in HK2 renal tubular epithelial cells, which indicates LMWF may result in an inhibition of the apoptosis pathway through reducing activity of MAPK pathways in a dose‐dependent manner. Our findings show LMWF ameliorates acute renal IRI via inhibiting MAPK signaling pathways in vivo and in vitro. This protective effect is attributed to the improvement of renal function, balance of oxidative stress and antioxidative defense and anti‐apoptosis. In summary. the results suggest that LMWF may serve as a potential therapeutic agent for acute renal IRI, and MAPK pathways, especially JNK/p38‐MAPK is an appealing therapeutic target for AKI.

Low Molecular Weight Fucoidan against Renal Ischemia–Reperfusion Injury via Inhibition of the MAPK Signaling Pathway

BackgroundIschemia reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) in both native and transplanted kidneys. The objective of the present study was to evaluate whether low-molecular-weight fucoidan (LMWF) could attenuate renal IRI in an animal model and in vitro cell models and study the mechanisms in which LMWF protected from IRI.Methodology/Principal FindingsMale mice were subjected to right renal ischemia for 30 min and reperfusion for 24 h, or to a sham operation with left kidney removed. Kidneys undergone IR showed characteristic morphological changes, such as tubular dilatation, and brush border loss. However, LMWF significantly corrected the renal dysfunction and the abnormal levels of MPO, MDA and SOD induced by IR. LMWF also inhibited the activation of MAPK pathways, which consequently resulted in a significant decrease in the release of cytochrome c from mitochondria, ratios of Bax/Bcl-2 and cleaved caspase-3/caspase-3, and phosphorylation of p53. LMWF alleviated hypoxia-reoxygenation or CoCl2 induced cell viability loss and ΔΨm dissipation in HK2 renal tubular epithelial cells, which indicates LMWF may result in an inhibition of the apoptosis pathway through reducing activity of MAPK pathways in a dose-dependent manner.Conclusions/SignificanceOur in vivo and in vitro studies show that LMWF ameliorates acute renal IRI via inhibiting MAPK signaling pathways. The data provide evidence that LMWF may serve as a potential therapeutic agent for acute renal IRI.

PDE5 inhibition against acute renal ischemia reperfusion injury in rats: does vardenafil offer protection?

To evaluate the effect of vardenafil on renal function after renal ischemia-reperfusion (IR) injury (IRI) in a rat model. Seventy-one Wistar rats were divided into 7 groups including (1) a vehicle-treated group, (2) a vehicle pretreated-IR group, (3-6) vardenafil pretreated-IR groups in doses of 0.02, 0.2, 2 and 20 μg/kg, respectively, (7) a group of IR followed by treatment with 2 μg/kg of vardenafil. Vardenafil or vehicle solution was administered one hour before unilateral nephrectomy and the induction of 45 min of ischemia on the contralateral kidney by clamping of renal pedicle. Four hours of reperfusion were allowed after renal ischemia. Studied parameters were serum creatinine, fractional excretion of sodium (FENa), and histological evaluation of renal specimens. In addition, renal tissue cGMP levels, ERK1/2 phosphorylation as well as renal function by renal scintigraphy were also evaluated. Administration of vardenafil before the induction of ischemia resulted in a significant reduction in creatinine and FENa levels as well as in less histological lesions observed in treated kidneys in comparison with the vehicle-treated group. The underlying mechanism of cytoprotection was cGMP depended and involved the phosphorylation of ERK proteins. Renal scintigraphy confirmed that PDE5 inhibition attenuates renal IRI. Vardenafil attenuates renal IRI. Based on similar results from relevant studies on other PDE-5 inhibitors in renal and cardiac IRI, it can be assumed that all PDE-5 inhibitors share a common mechanism of cytoprotection.

Protective Effects of Exogenous Interleukin 18–Binding Protein in a Rat Model of Acute Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion (I/R) renal injury is considered the most common cause of acute kidney injury (AKI). The pathophysiology of I/R AKI involves a complex interplay among tubular epithelial cell injury, microcirculation dysfunction, and inflammation. Interleukin 18-binding protein (IL-18BP) is a natural inhibitor of IL-18 a cytokine that plays an important role in the pathogenesis of AKI. Therefore, we hypothesized that exogenous IL-18BP could protect against renal injuries after kidney I/R. Male Sprague-Dawley rats were divided into three groups: a sham operation group, I/R with vehicle injection, and I/R with IL-18BP injection. Rats underwent bilateral renal pedicle clamping, and IL-18BP or vehicle was administered just before reperfusion. Rats were killed 6, 24, and 72 h after reperfusion. After IL-18BP treatment, renal tubule epithelium showed reduced apoptosis and enhanced proliferation. For peritubular capillary (PTC) endothelium, apoptosis was inhibited, and there was an increase in PTC endothelium density. Macrophage infiltration was inhibited, and inflammatory cytokines were downregulated. Increased expression of vascular endothelial growth factor and decreased expression of thrombospondin 1 were also observed. Exogenous IL-18BP attenuated renal injury caused by I/R via inhibiting inflammation in the renal tissue and protecting tubular epithelium and PTC endothelium.

Hydroxyfasudil-Mediated Inhibition of ROCK1 and ROCK2 Improves Kidney Function in Rat Renal Acute Ischemia-Reperfusion Injury

Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the important role of cytoskeletal reorganization, mainly regulated by RhoGTPases, in the development of IRI we hypothesized that a preventive, selective inhibition of the Rho effector Rho-associated coiled coil containing protein kinase (ROCK) by hydroxyfasudil may improve renal IRI outcome. Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals. In addition, renal perfusion (as assessed by 18F-fluoride Positron Emission Tomography (PET)), creatinine- and urea-clearances improved significantly. Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, 18F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis. We conclude from our study that ROCK-inhibition by hydroxyfasudil significantly improves kidney function in a rat model of acute renal IRI and is therefore a potential new therapeutic option in humans.

Brain Natriuretic Peptide is Not Reno-Protective during Renal Ischemia-Reperfusion Injury in the Rat

Acute kidney injury (AKI) occurs in 30% of patients undergoing complex cardiovascular surgery, and renal ischemia-reperfusion (I/R) injury is often a contributing factor. A recent meta-analysis observed that perioperative natriuretic peptide administration was associated with a reduction in AKI requiring dialysis in cardiovascular surgery patients. This study was designed to further clarify the potential reno-protective effect of brain natriuretic peptide (BNP) using an established rat model of renal I/R injury. The study comprised three groups (n = 10 kidneys each): (1) control (no injury); (2) I/R injury (45 min of bilateral renal ischemia followed by 3 h of reperfusion); and (3) BNP (I/R injury plus rat-BNP pretreatment at 0.01 μg/kg/min). Glomerular filtration rate (GFR) and a biomarker of AKI, urinary neutrophil gelatinase-associated lipocalin (uNGAL), were measured at baseline and at 30 minute intervals post-ischemia. Groups were compared using two-way repeated measures analysis of variance (mean ± SD, significance P < 0.05). Baseline GFR measurements for control, I/R, and BNP groups were 1.07 ± 0.55, 0.88 ± 0.51, and 1.03 ± 0.59 mL/min (P = 0.90), respectively. Post-ischemia, GFR was significantly lower in I/R and BNP compared with controls at 30 min, 1.29 ± 0.97, 0.08 ± 0.04, and 0.06 ± 0.05 mL/min (P < 0.01), and remained lower through 3 h, 1.79 ± 0.44, 0.30 ± 0.17, and 0.32 ± 0.12 mL/min (P < 0.01). Comparing I/R to BNP groups, GFR did not differ significantly at any time point. There was no significant difference in uNGAL levels at 1 h (552 ± 358 versus 516 ± 259 ng/mL, P = 0.87) or 2 h (1073 ± 589 versus 989 ± 218 ng/mL, P = 0.79) between I/R and BNP. BNP does not reduce the renal injury biomarker, urinary NGAL, or preserve GFR in acute renal ischemia-reperfusion injury.

FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury

Acute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-alpha (TNF-alpha) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-alpha and interleukin-1beta production, may reduce IRI. IRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2Nx90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2Nx90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia. Three WI90 animals (43%) and five 1/2Nx90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-alpha protein expression was diminished in FR-treated groups. This is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.

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

Mechanisms of action of recombinant human activated protein C

Human activated protein C (APC) is a serineprotease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC. The administration of recombinant human activated protein C (rhAPC), drotrecogin alfa (activated), Xigris, to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials. Anti-apoptotic and immunomodulatory effects of rhAPC have been examined in in vitro experiments and in experimental animal studies. Moreover, a reduction of endothelial cell permeability, enhanced endothelial cell survival as well as improvements of microcirculatory disorders have been proposed for rhAPC. The manifold mechanisms of action of APC may give reasons for its application in diseases other than sepsis, which are characterized by endothelial and microcirculatory dysfunction, e.g. acute pulmonary or renal failure, ischemic stroke, ischemia-reperfusion injury and acute pancreatitis. A better understanding of the anti-inflammatory, anti-apoptotic and immunomodulatory modes of action of APC could be relevant for dosing and mode of application and may lead to a broadening of the indication field for rhAPC.

The role of serum C-reactive protein in acute ischemicreperfusion injury of kidney

Objective Blocking early C-reactive protein-mediated inflammatory reaction may have therapeutic implications in improving the prognosis of acute renal failure with severe ischemic-reperfusion injury. Therefore, the role of serum C-reactive protein in acute renal ischemic-reperfusion injury was investigated. Methods Fourteen New Zealand albino rabbits were selected and divided into a treated and a control group at random. An acute renal ischemia-reperfusion injury model was induced by clamping the right renal artery for 45 minutes with simultaneous contralateral nephrectomy, followed by right renal reperfusion. The treated group was injected with dexamethasone (1 mg/kg) 2 minutes before renal reperfusion. Serum C-reactive protein, blood urea nitrogen, creatinine, and urine volume were recorded at designed time phases in both groups. Data were expressed as mean ± standard deviation and analyzed using the Student's t test. Results In the control group, there was a steady increase of serum C-reactive protein that reached its peak at 6-hour reperfusion, and a positive correlation between C-reactive protein and blood urea nitrogen and creatinine (r = 0.62 and 0.53, respectively); there was a negative correlation between C-reactive protein and urine volume (r = −0.52). Compared with the control group, C-reactive protein values in the treated group remained mainly in the baseline levels after reperfusion, with C-reactive protein peaking at 4-hour reperfusion (p<0.01), whereas urine volume increased significantly (p<0.01). Conclusion This study indicates that C-reactive protein is involved in the pathogenesis of acute renal ischemic-reperfusion injury; blocking early C-reactive protein-mediated inflammatory reaction may have therapeutic implications in improving the prognosis of acute renal failure with severe ischemic-reperfusion injury.