Interleukin-19 Mediates Tissue Damage in Murine Ischemic Acute Kidney Injury

Inflammation and renal tubular injury are major features of acute kidney injury (AKI). Many cytokines and chemokines are released from injured tubular cells and acts as proinflammatory mediators. However, the role of IL-19 in the pathogenesis of AKI is not defined yet. In bilateral renal ischemia/reperfusion injury (IRI)-induced and HgCl₂-induced AKI animal models, real-time quantitative (RTQ)-PCR showed that the kidneys, livers, and lungs of AKI mice expressed significantly higher IL-19 and its receptors than did sham control mice. Immunohistochemical staining showed that IL-19 and its receptors were strongly stained in the kidney, liver, and lung tissue of AKI mice. In vitro, IL-19 upregulated MCP-1, TGF-β1, and IL-19, and induced mitochondria-dependent apoptosis in murine renal tubular epithelial M-1 cells. IL-19 upregulated TNF-α and IL-10 in cultured HepG2 cells, and it increased IL-1β and TNF-α expression in cultured A549 cells. In vivo, after renal IRI or a nephrotoxic dose of HgCl₂ treatment, IL-20R1-deficient mice (the deficiency blocks IL-19 signaling) showed lower levels of blood urea nitrogen (BUN) in serum and less tubular damage than did wild-type mice. Therefore, we conclude that IL-19 mediates kidney, liver, and lung tissue damage in murine AKI and that blocking IL-19 signaling may provide a potent therapeutic strategy for treating AKI.     

Vitamin D Deficiency Aggravates Chronic Kidney Disease Progression after Ischemic Acute Kidney Injury

Background

Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-β1 (TGF-β1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD).

Methods

Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-β, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and α-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area.

Results

IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and α-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-β1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals.

Conclusion

Through inflammatory pathways and involvement of TGF-β1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.     

Augmenting Autophagy to Treat Acute Kidney Injury during Endotoxemia in Mice

Objective

To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice.

Design

Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI).

Setting

Academic research laboratory.

Subjects

C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age.

Intervention

Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg). Measurements and Main Results: Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI.

Conclusions

These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease.     

Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice

Ischemia-reperfusion induced acute kidney injury (IR-AKI) is widely used as a model of AKI in mice, but results are often quite variable with high, often unreported mortality rates that may confound analyses. Bilateral renal pedicle clamping is commonly used to induce IR-AKI, but differences between effective clamp pressures and/or renal responses to ischemia between kidneys often lead to more variable results. In addition, shorter clamp times are known to induce more variable tubular injury, and while mice undergoing bilateral injury with longer clamp times develop more consistent tubular injury, they often die within the first 3 days after injury due to severe renal insufficiency. To improve post-injury survival and obtain more consistent and predictable results, we have developed two models of unilateral ischemia-reperfusion injury followed by contralateral nephrectomy. Both surgeries are performed using a dorsal approach, reducing surgical stress resulting from ventral laparotomy, commonly used for mouse IR-AKI surgeries. For induction of moderate injury BALB/c mice undergo unilateral clamping of the renal pedicle for 26 min and also undergo simultaneous contralateral nephrectomy. Using this approach, 50-60% of mice develop moderate AKI 24 hr after injury but 90-100% of mice survive. To induce more severe AKI, BALB/c mice undergo renal pedicle clamping for 30 min followed by contralateral nephrectomy 8 days after injury. This allows functional assessment of renal recovery after injury with 90-100% survival. Early post-injury tubular damage as well as post injury fibrosis are highly consistent using this model.     

运动性急性肾损伤与新型肾功能生物标志物

大强度运动中,非创伤性急性肾损伤（acute kindey injury, AKI）经常发生,表现为血尿、蛋白尿、血红蛋白尿等。一般认为,中低程度的运动性急性肾损伤是可逆的,可完全恢复。但动物实验与人类研究均发现,严重的运动性肾损伤会导致“功能性”急性肾损伤发展为“结构性”急性肾损伤,并增加慢性肾病的风险。运动性急性肾损伤对机体的潜在健康威胁已引起国内外相关领域学者的广泛关注。血清肌酐 (serum creatinine, Scr)和尿量作为肾功能的传统经典标志物,不能特异性反映早期肾损伤,而新型肾损伤标志物可进一步明确损伤的位置及严重程度。在运动领域,利用新型生物标志物进行无创性检查,识别早期运动性急性肾损伤非常必要。本文综述了反映肾小球或肾小管损伤、细胞周期停滞和肾损伤修复的新型生物标志物,着重论述了尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL)和肾损伤分子-1（KIM-1)与肾功能的关系,以及长时间耐力运动、急性运动和高强度间歇阻力运动3种运动形式对肾功能的影响,旨在引起重视,精准识别风险,及时进行早干预。     

Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury

Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3(+) T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3(+)CD8(+) phenotype; however, both CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (T(nu/nu)) mice. Adoptive transfer of murine wild-type T lymphocytes into T(nu/nu) mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney-lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.     

运动性急性肾损伤与新型肾功能生物标志物

大强度运动中,非创伤性急性肾损伤（acute kindey injury, AKI）经常发生,表现为血尿、蛋白尿、血红蛋白尿等。一般认为,中低程度的运动性急性肾损伤是可逆的,可完全恢复。但动物实验与人类研究均发现,严重的运动性肾损伤会导致“功能性”急性肾损伤发展为“结构性”急性肾损伤,并增加慢性肾病的风险。运动性急性肾损伤对机体的潜在健康威胁已引起国内外相关领域学者的广泛关注。血清肌酐 (serum creatinine, Scr)和尿量作为肾功能的传统经典标志物,不能特异性反映早期肾损伤,而新型肾损伤标志物可进一步明确损伤的位置及严重程度。在运动领域,利用新型生物标志物进行无创性检查,识别早期运动性急性肾损伤非常必要。本文综述了反映肾小球或肾小管损伤、细胞周期停滞和肾损伤修复的新型生物标志物,着重论述了尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL)和肾损伤分子-1（KIM-1)与肾功能的关系,以及长时间耐力运动、急性运动和高强度间歇阻力运动3种运动形式对肾功能的影响,旨在引起重视,精准识别风险,及时进行早干预。     

Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice

Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.     

Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury

Neurochemical Research - Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD+ precursor,...     

Linking Injury to Outcome in Acute Kidney Injury: A Matter of Sensitivity

Current consensus definitions of Acute Kidney Injury (AKI) utilise thresholds of change in serum or plasma creatinine and urine output. Biomarkers of renal injury have been validated against these definitions. These biomarkers have also been shown to be independently associated with mortality and need for dialysis. For AKI definitions to include these structural biomarkers, there is a need for an independent outcome against which to judge both markers of functional change and structural markers of injury. We illustrate how sensitivity to need for dialysis and death can be used to link functional and structural (biomarker) based definitions of AKI. We demonstrated the methodology in a representative cohort of critically ill patients, in which an increase of plasma creatinine of >26.4 µmol/L in 48 hours or >50% in 7 days (Functional-AKI) had a sensitivity of 62% for death or dialysis within 30 days. In a development sub-cohort the urinary neutrophil-gelatinase-associated-lipocalin threshold with a 62% sensitivity for death or dialysis was 140 ng/ml (Structural-AKI). Using these thresholds in a validation sub-cohort, the risk of death or dialysis relative to those with no AKI by either definition was, for combined Structural-AKI and Functional-AKI 3.11 (95% Confidence interval: 2.53 to 3.55), for those with Structural-AKI but not Functional-AKI 1.51 (1.26 to 1.62), and for those with Functional-AKI but not Structural-AKI 1.34 (1.16 to 1.42). Linking functional and structural biomarkers via sensitivity for death and dialysis is a viable method by which to define thresholds for novel biomarkers of AKI.     

Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice

Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.     

Clinical Risk Scoring Models for Prediction of Acute Kidney Injury after Living Donor Liver Transplantation: A Retrospective Observational Study

Acute kidney injury (AKI) is a frequent complication of liver transplantation and is associated with increased mortality. We identified the incidence and modifiable risk factors for AKI after living-donor liver transplantation (LDLT) and constructed risk scoring models for AKI prediction. We retrospectively reviewed 538 cases of LDLT. Multivariate logistic regression analysis was used to evaluate risk factors for the prediction of AKI as defined by the RIFLE criteria (RIFLE = risk, injury, failure, loss, end stage). Three risk scoring models were developed in the retrospective cohort by including all variables that were significant in univariate analysis, or variables that were significant in multivariate analysis by backward or forward stepwise variable selection. The risk models were validated by way of cross-validation. The incidence of AKI was 27.3% (147/538) and 6.3% (34/538) required postoperative renal replacement therapy. Independent risk factors for AKI by multivariate analysis of forward stepwise variable selection included: body-mass index >27.5 kg/m² [odds ratio (OR) 2.46, 95% confidence interval (CI) 1.32–4.55], serum albumin <3.5 mg/dl (OR 1.76, 95%CI 1.05–2.94), MELD (model for end-stage liver disease) score >20 (OR 2.01, 95%CI 1.17–3.44), operation time >600 min (OR 1.81, 95%CI 1.07–3.06), warm ischemic time >40 min (OR 2.61, 95%CI 1.55–4.38), postreperfusion syndrome (OR 2.96, 95%CI 1.55–4.38), mean blood glucose during the day of surgery >150 mg/dl (OR 1.66, 95%CI 1.01–2.70), cryoprecipitate > 6 units (OR 4.96, 95%CI 2.84–8.64), blood loss/body weight >60 ml/kg (OR 4.05, 95%CI 2.28–7.21), and calcineurin inhibitor use without combined mycophenolate mofetil (OR 1.87, 95%CI 1.14–3.06). Our risk models performed better than did a previously reported score by Utsumi et al. in our study cohort. Doses of calcineurin inhibitor should be reduced by combined use of mycophenolate mofetil to decrease postoperative AKI. Prospective randomized trials are required to address whether artificial modification of hypoalbuminemia, hyperglycemia and postreperfusion syndrome would decrease postoperative AKI in LDLT.     

Hsp72 Is a Novel Biomarker to Predict Acute Kidney Injury in Critically Ill Patients

Background and Objectives

Acute kidney injury (AKI) complicates the course of disease in critically ill patients. Efforts to change its clinical course have failed because of the fail in the early detection. This study was designed to assess whether heat shock protein (Hsp72) is an early and sensitive biomarker of acute kidney injury (AKI) compared with kidney injury molecule (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) biomarkers.

Methods

A total of 56 critically ill patients fulfilled the inclusion criteria. From these patients, 17 developed AKI and 20 were selected as controls. In AKI patients, Kim-1, IL-18, NGAL, and Hsp72 were measured from 3 days before and until 2 days after the AKI diagnosis and in no-AKI patients at 1, 5 and 10 days after admission. Biomarker sensitivity and specificity were determined. To validate the results obtained with ROC curves for Hsp72, a new set of critically ill patients was included, 10 with AKI and 12 with no-AKI patients.

Results

Urinary Hsp72 levels rose since 3 days before the AKI diagnosis in critically ill patients; this early increase was not seen with any other tested biomarkers. Kim-1, IL-18, NGAL, and Hsp72 significantly increased from 2 days before AKI and remained elevated during the AKI diagnosis. The best sensitivity/specificity was observed in Kim-1 and Hsp72: 83/95% and 100/90%, respectively, whereas 1 day before the AKI diagnosis, the values were 100/100% and 100/90%, respectively. The sensibility, specificity and accuracy in the validation test for Hsp72 were 100%, 83.3% and 90.9%, respectively.

Conclusions

The biomarker Hsp72 is enough sensitive and specific to predict AKI in critically ill patients up to 3 days before the diagnosis.     

The Effect of Hypothermia Therapy on Cortical Laminar Disruption following Ischemic Injury in Neonatal Mice

Hypothermia has been proposed as a treatment for reducing neuronal damage in the brain induced by hypoxic ischemia. In the developing brain, hypoxic ischemia-induced injury may give rise to cerebral palsy (CP). However, it is unknown whether hypothermia might affect the development of CP. The purpose of this study was to investigate whether hypothermia would have a protective effect on the brains of immature, 3-day old (P3) mice after a challenge of cerebral ischemia. Cerebral ischemia was induced in P3 mice with a right common carotid artery ligation followed by hypoxia (6% O₂, 37°C) for 30 min. Immediately after hypoxic ischemia, mice were exposed to hypothermia (32°C) or normothermia (37°C) for 24 h. At 4 weeks of age, mouse motor development was tested in a behavioral test. Mice were sacrificed at P4, P7, and 5 weeks to examine brain morphology. The laminar structure of the cortex was examined with immunohistochemistry (Cux1/Ctip2); the number of neurons was counted; and the expression of myelin basic protein (MBP) was determined. The hypothermia treatment was associated with improved neurological outcomes in the behavioral test. In the normothermia group, histological analyses indicated reduced numbers of neurons, reduced cortical laminar thickness in the deep, ischemic cortical layers, and significant reduction in MBP expression in the ischemic cortex compared to the contralateral cortex. In the hypothermia group, no reductions were noted in deep cortical layer thickness and in MBP expression in the ischemic cortex compared to the contralateral cortex. At 24 h after the hypothermia treatment prevented the neuronal cell death that had predominantly occurred in the ischemic cortical deep layers with normothermia treatment. Our findings may provide a preclinical basis for testing hypothermal therapies in patients with CP induced by hypoxic ischemia in the preterm period.     

Culture-Modified Bone Marrow Cells Attenuate Cardiac and Renal Injury in a Chronic Kidney Disease Rat Model via a Novel Antifibrotic Mechanism

Background

Most forms of chronic kidney disease are characterized by progressive renal and cardiac fibrosis leading to dysfunction. Preliminary evidence suggests that various bone marrow-derived cell populations have antifibrotic effects. In exploring the therapeutic potential of bone marrow derived cells in chronic cardio-renal disease, we examined the anti-fibrotic effects of bone marrow-derived culture modified cells (CMCs) and stromal cells (SCs).

Methodology/Principal Findings

In vitro, CMC-conditioned medium, but not SC-conditioned medium, inhibited fibroblast collagen production and cell signalling in response to transforming growth factor-ß. The antifibrotic effects of CMCs and SCs were then evaluated in the 5/6 nephrectomy model of chronic cardio-renal disease. While intravascular infusion of 10⁶ SCs had no effect, 10⁶ CMCs reduced renal fibrosis compared to saline in the glomeruli (glomerulosclerosis index: 0.8±0.1 v 1.9±0.2 arbitrary units) and the tubulointersitium (% area type IV collagen: 1.2±0.3 v 8.4±2.0, p<0.05 for both). Similarly, 10⁶ CMCs reduced cardiac fibrosis compared to saline (% area stained with picrosirius red: 3.2±0.3 v 5.1±0.4, p<0.05), whereas 10⁶ SCs had no effect. Structural changes induced by CMC therapy were accompanied by improved function, as reflected by reductions in plasma creatinine (58±3 v 81±11 µmol/L), urinary protein excretion (9×/÷1 v 64×/÷1 mg/day), and diastolic cardiac stiffness (left ventricular end-diastolic pressure-volume relationship: 0.030±0.003 v 0.058±0.011 mm Hg/µL, p<0.05 for all). Despite substantial improvements in structure and function, only rare CMCs were present in the kidney and heart, whereas abundant CMCs were detected in the liver and spleen.

Conclusions/Significance

Together, these findings provide the first evidence suggesting that CMCs, but not SCs, exert a protective action in cardio-renal disease and that these effects may be mediated by the secretion of diffusible anti-fibrotic factor(s).     

急性铅应激诱导肝肾损伤及其分子机制初探

利用腹腔注射醋酸铅方法构建了铅染毒小鼠(Mus muscculus)模型,观察了染毒小鼠肝、肾的组织学变化,并通过免疫组织化学方法检测了染毒小鼠肝、肾组织中Caspase-3、Bcl-2和Bax蛋白的表达量.结果发现,急性铅染毒可诱导肝和肾组织学损伤,且在诱导肝细胞和肾细胞凋亡、损伤过程中,随时间的延长,Caspase-3的表达量逐渐增加,而Bcl-2与Bax两蛋白表达量的比值呈逐渐下降趋势,有一定的时效性,染毒48 h后,与对照组相比,均差异极显著,表明铅可能通过影响Caspase-3、Bcl-2和Bax的表达而诱导肝和肾细胞异常凋亡.     

创伤患者急性肾功能损伤诊断与治疗

目的:探讨患者创伤后发生急性肾损伤的患者发病率、临床特点以及发病危险因素,以便有效预防和及早治疗。方法:回顾性分析我院重症监护室2004年1月至2010年12月收治的创伤患者相关临床资料,分析创伤后急性肾损伤的发病率以及发病危险因素。结果:共有106例患者纳入我们的研究,其中47例患者创伤后并发急性肾损伤。在发生急性肾损伤患者中,平均年龄为31±19岁,84.6%为男性;其中25例为脓毒血症引起,18例是因为低血压导致急性肾功能损伤。所有患者中,24例患者出现了少尿的症状,19例患者进行了透析治疗。腹部外伤[(OR)=3.66,P=0.027]和应用呋塞米[(OR=4.10,P=0.026)]是发生急性肾损伤的危险因素。结论:急性肾损伤时创伤后的严重并发症之一,死亡率高。只有找到创伤后发生急性肾损伤的危险因素,才能有效预防和及早治疗。     

Increased Cellular Senescence and Vascular Rarefaction Exacerbate the Progression of Kidney Fibrosis in Aged Mice Following Transient Ischemic Injury

Recent findings indicate that elderly patients with acute kidney injury (AKI) have an increased incidence of progression to chronic kidney disease (CKD) due to incomplete recovery from an acute insult. In the current study, a co-morbid model of AKI was developed to better mimic the patient population and to investigate whether age exacerbates the fibrosis and inflammation that develop in the sequelae of progressive kidney disease following acute injury. Young (8–10 weeks) and aged (46–49 weeks) C57BL/6 mice were subjected to 30 min bilateral renal ischemia-reperfusion (I/R) to induce AKI. The aged animals have greater mortality and prolonged elevation of plasma creatinine correlating with less tubular epithelial cell proliferation compared to the young. Six weeks post-reperfusion, interstitial fibrosis is greater in aged kidneys based on picrosirius red staining and immunolocalization of cellular fibronectin, collagen III and collagen IV. Aged kidneys 6 weeks post-reperfusion also express higher levels of p53 and p21 compared to the young, correlating with greater increases in senescence associated (SA) β-galactosidase, a known marker of cellular senescence. A higher influx of F4/80⁺ macrophages and CD4⁺ T lymphocytes is measured and is accompanied by increases in mRNA of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). Importantly, microvascular density is significantly less, correlating with an increase in nitro-tyrosine, a marker of oxidative stress. Collectively, these data demonstrate that prolonged acute injury in the aged animals results in an accelerated progression of kidney disease in a chronic state.     

Pressure Controlled Ventilation to Induce Acute Lung Injury in Mice

Murine models are extensively used to investigate acute injuries of different organs systems (1-34). Acute lung injury (ALI), which occurs with prolonged mechanical ventilation, contributes to morbidity and mortality of critical illness, and studies on novel genetic or pharmacological targets are areas of intense investigation (1-3, 5, 8, 26, 30, 33-36). ALI is defined by the acute onset of the disease, which leads to non-cardiac pulmonary edema and subsequent impairment of pulmonary gas exchange (36). We have developed a murine model of ALI by using a pressure-controlled ventilation to induce ventilator-induced lung injury (2). For this purpose, C57BL/6 mice are anesthetized and a tracheotomy is performed followed by induction of ALI via mechanical ventilation. Mice are ventilated in a pressure-controlled setting with an inspiratory peak pressure of 45 mbar over 1 - 3 hours. As outcome parameters, pulmonary edema (wet-to-dry ratio), bronchoalveolar fluid albumin content, bronchoalveolar fluid and pulmonary tissue myeloperoxidase content and pulmonary gas exchange are assessed (2). Using this technique we could show that it sufficiently induces acute lung inflammation and can distinguish between different treatment groups or genotypes (1-3, 5). Therefore this technique may be helpful for researchers who pursue molecular mechanisms involved in ALI using a genetic approach in mice with gene-targeted deletion.